About

Stephen J. Schuster, M.D., is the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma at the University of Pennsylvania. He serves as an Attending Physician in the Department of Medicine, Division of Hematology-Oncology at the Hospital of the University of Pennsylvania. Dr. Schuster is also the Director of Lymphoma Translational Research at the Abramson Cancer Center of the University of Pennsylvania. His research and clinical focus are centered on lymphoma, including chronic lymphocytic leukemia, and he is involved in clinical care and research related to these areas.

Research topics

• Medicine
• Internal medicine
• Immunology
• Mathematics
• Oncology
• Cancer research

Selected publications

• Early administration of CD20 x CD3 bispecific antibodies 4-6 weeks after CAR-T infusion for patients with residual or progressive large B cell lymphomas

  Blood · 2025-11-03

  articleOpen accessSenior author

  Abstract Background: CD19-directed CAR T-cell therapy (CAR-T) has improved outcomes and altered the treatment landscape for patients with relapsed/refractory large B-cell lymphomas (r/r LBCL). Despite these improvements, 60-70% of patients do not have long term remissions after CAR-T. CD20 x CD3 bispecific antibodies (BsAbs), such as mosunetuzumab and glofitamab, have demonstrated efficacy in LBCL relapsing after CAR-T (Chong Blood Advances 2025). We hypothesized that BsAbs could enhance the efficacy of CAR-T by reducing antigen-negative escape and enhancing CAR-T cell activation and persistence. To evaluate this hypothesis, we designed a phase IIa trial of early administration of mosunetuzumab or glofitamab within 31-45 days of CAR T-cell infusion. Methods: This is a multi-center clinical trial of early administration of BsAb for patients with r/r LBCL who receive standard of care CAR-T and have a partial response (PR), stable disease (SD), or progressive disease (PD) at day 30 post CAR-T infusion. BsAb is administered day 31-45 post CAR-T. Patients receive 2 cycles of BsAb (Cohort 1, mosunetuzumab; Cohort 2, glofitamab) and are assessed for response. Patients with complete response (CR) or PD after 2 cycles of BsAb discontinue BsAb; patients with PR or SD are continue BsAb every 3 weeks for up to 1 year and every 24 months during the second year. Efficacy is measured by the CR rate at 24 weeks after initiation of BsAb. CAR-T expansion in blood is assessed by qPCR. Enrollment to Cohort 1 (mosunetuzumab) is complete and Cohort 2 (glofitamab) enrollment is ongoing (NCT04889716). Results: Eight patients, 5 male and 3 female, with a median age of 63 years (range 47-78) were enrolled between January 2022 and May 2025, and included 7 patients with diffuse large B-cell lymphoma NOS (GCB-like [n=4], ABC-like [n=2]) and 1 patient with high grade B-cell lymphoma (double-hit). Patients had a median of 3 prior lines of therapy (range 2-7); 5 patients were primary refractory, 6 patients had extranodal disease, and 5 patients had elevated LDH at CAR-T infusion. Prior CAR-T products included tisagenlecleucel (n-2) and lisocabtagene maraleucel (n=6). The median time from CAR-T cell infusion to BsAb treatment was 42 days (range 33-45). Pre-BsAb responses to CAR-T at Day 30 included 4 PR, 1 SD, 3 PD. Within 30 days after CAR-T infusion and prior to treatment with BsAb, three patients had cytokine release syndrome (CRS) (n=2, grade 1; n=1, grade 2); no ICANS was observed. Mosunetuzumab (n=6) was generally well tolerated; CRS occurred in 3 of the 6 (50%) patients and was low grade (n=2, grade 1; n=1 grade 2). One patient received corticosteroids. One patient had a grade > 3 adverse event related to mosunetuzumab (2 episodes of grade 4 neutropenia, which responded to G-CSF and delay of mosunetuzumab). No CRS occurred in the 2 patients who received glofitamab. No patients developed ICANS. No unexpected adverse events have occurred. The best overall response rate (ORR) in the mosunetuzumab cohort (n=6) was 67% (1 CR, 3 PR, 2 SD, 1 PD). Four patients improved their CAR-T response status after the addition of mosunetuzumab (1 PD to SD, 2 SD/PD to PR, and 1 PR to CR). At 24 weeks, the best ORR was 50% (1 CR, 2 PR, 3 PD). With median follow-up of over 3 years, 1 year progression-free survival is 33% (95%CI 5-68); 1 year duration of response is 50% (95%CI 6-84). Response assessment in the glofitamab cohort is forthcoming. We also assessed changes in T cells and CAR-T cells in both cohorts. After starting BsAb, CAR-T cells in peripheral blood increased between cycle 1 day 1 and cycle 1 day 8 in 5/7 patients with available data; median fold change in CAR-T expansion was 0.25 (25% increase) copies/ug gDNA (range -0.42-12.62). Two patients with responses to mosunetuzumab had undetectable CAR-T at baseline and developed detectable CAR-T by cycle 1 day 8. All patients who continued to receive bispecific antibodies (5/7), had detectable CAR transgene at 12 weeks to 3 months. Two patients underwent biopsy at PD; both tumors expressed CD19 and CD20 and had minimal to no infiltration by T cells. Additional samples are undergoing evaluation and will be presented at the meeting. Conclusions: Early administration of CD20 x CD3 bispecific antibodies after CAR-T appears safe and may enhance CAR-T expansion. The sequential combination of CD19 and CD20 targeted therapies may improve clinical responses in certain patients with r/r LBCL.

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• Fixed-duration subcutaneous mosunetuzumab continues to demonstrate high rates of durable responses in patients with relapsed/refractory follicular lymphoma after ≥2 prior therapies: 3-year follow-up from a pivotal Phase II study

  Blood · 2025-11-03

  articleOpen access

  Abstract Background: In a pivotal Phase II study (NCT02500407), subcutaneous (SC) mosunetuzumab (Mosun), a CD20xCD3 T-cell engaging bispecific antibody, achieved high response rates and durable remissions, and demonstrated pharmacokinetic non-inferiority to the intravenous (IV) formulation in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) after ≥2 prior lines of therapy, including those with high-risk features (Bartlett et al. ASH 2024; Hess et al. EHA 2025). We report updated efficacy and safety data from the pivotal Phase II study of Mosun SC in pts with R/R FL after three years of follow-up. Methods: Pts had R/R FL Grade (Gr) 1–3a and ≥2 prior therapies. Fixed-duration Mosun SC was administered (≤1mL volume) in 21-day cycles with step-up dosing in Cycle (C)1 (C1 Day [D]1, 5mg; C1D8, 45mg; C1D15, 45mg; C2D1 onwards, 45mg). Hospitalization was not mandatory. Pts with a complete response (CR) by C8 completed treatment without additional cycles; those with a partial response or stable disease could continue therapy for up to 17 cycles. Pts who achieved a CR with initial treatment and relapsed after the end of treatment were eligible for re-treatment. Responses were assessed per Cheson 2007 criteria. CR rate, overall response rate (ORR), duration of (complete) response (DO[C]R), progression-free survival (PFS) and overall survival (OS), and safety endpoints were investigator-assessed. Time to next treatment (TTNT) and response to re-treatment were exploratory endpoints. Results: Ninety-four pts were enrolled in this pivotal cohort; median age was 65 years (range: 35–84), 87% had Ann Arbor Stage III/IV disease, 66% were refractory to prior anti-CD20 therapy, 43% had progressed within 24 months from start of first-line treatment (POD24), 30% had elevated lactate dehydrogenase, and 23% had bulky disease (>7cm). As of May 1, 2025, median follow-up was 35.5 months (range: 1–48). The ORR and CR rate in the overall population were 74% and 63%, respectively. Median DOR and DOCR were 25.1 months (95% confidence interval [CI]: 21–39) and 33.6 months (95% CI: 22–not estimable [NE]), respectively. Median PFS was 18.5 months (95% CI: 11–28) and median OS was not reached (95% CI: NE); the estimated 30-month PFS and OS rates were 37% (95% CI: 27–48) and 83% (95% CI: 75–91), respectively. Median TTNT was 39.7 months (95% CI: 36–NE). In 59 pts with a CR, the 30-month PFS and OS rates were 56% (95% CI: 42–69) and 92% (95% CI: 85–100), respectively, and median PFS was 35.9 months (95% CI: 25–NE). Of 9 pts re-treated with Mosun, 7 (78%) responded, and 6 (67%) achieved a CR. At the clinical cut-off date, 4/7 re-treated pts with a response remained in remission. In pts with POD24, the ORR and CR rates were 70% and 58%, respectively. Median PFS was 15.7 months (95% CI: 6–NE) and the 30-month PFS rate was 41% (95% CI: 25–57). In pts with bulky disease, the ORR was 68% and CR rate was 55%. Median PFS was 28.3 months (95% CI: 6–NE) and the 30-month PFS rate was 42% (95% CI: 18–66), though few pts remained at risk. No new cytokine release syndrome (CRS) events or fatal, serious, or Gr ≥3 adverse events (AEs) were reported since the previous analysis. Injection site reactions remained the most common AE (69%). Fatal AEs occurred in 5 pts (COVID-19 pneumonia, n=2; COVID-19, n=1; hemophagocytic lymphohistiocytosis, n=1 [with active Epstein-Barr virus, cytomegalovirus, and lymphoma transformation]; general physical health deterioration, n=1). CRS events occurred in 30% of pts (Gr 3: n=2) and all resolved. Infections were reported in 55% of pts (Gr 1/2: 36%; Gr 3/4: 16%; Gr 5: 3%). Gr 3 febrile neutropenia was reported in 2 pts. No immune effector cell-associated neurotoxicity syndrome events were reported. The safety profile during re-treatment was consistent with initial therapy, with only 2 (10%) Gr 1 CRS events, 1 serious AE, and no fatal AEs. Conclusions: In this updated analysis, with a median follow-up of 35.5 months, fixed-duration Mosun SC continued to demonstrate durable responses, similar to those previously reported for Mosun IV in a comparable patient population. The safety profile was manageable with low rates of CRS and infections, consistent with previous analyses. Mosun SC has a favorable benefit-risk profile with the convenience of outpatient accessibility and short administration times.

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• Data from DLBCL Cells Emerge after CD19 CAR T Cells with Cross-Antigen Resistance and a Gene Signature Predictive of Clinical CAR T-cell Response

  2025-11-03

  articleOpen access

  <div>Abstract<p>Current understanding of lymphoma cell-intrinsic mechanisms of relapse following chimeric antigen receptor (CAR) T-cell treatment of diffuse large B-cell lymphoma (DLBCL) include antigen loss and apoptosis resistance. Herein, CD19 CAR T-cell response and resistance were modeled, and it was identified that treatment-naïve CD19 expression does not correlate with CAR T-cell sensitivity, but resistance is frequently accompanied by reversible downregulation of CD19 that once restored is not paralleled with restored sensitivity to CAR T cell–mediated killing. Profiling a suite of DLBCL cell lines to CD19 CAR T-cell sensitivity reveals that DLBCL cells become nonresponsive to CAR T cell–killing, including to alternative antigen targeting of CD20 or CD22. Leveraging these resistant models, we identified gene signatures present in the CAR T cell–resistant DLBCL cell lines that correlate with patient response to CTL019 in two independent clinical trials. Finally, we show that combination strategies to overcome this resistance, including up-front dual-antigen targeting and combined treatment with an Mcl-1 inhibitor, improve CAR T-cell responses.</p>Significance:<p>We demonstrate that DLBCL cells surviving CD19 CAR T-cell treatment develop a resistance phenotype with a “resistance signature” predictive of clinical CAR T-cell response, mediating cross-resistance between CAR T cells targeting different antigens. Our findings suggest that up-front dual-antigen targeting and combination therapies could improve clinical outcomes.</p></div>

  PublisherDOI

• Activity of autologous anti-CD19 chimeric antigen receptor T-cell therapy in CD19-negative large B-cell lymphoma: A cell therapy consortium real world experience

  Blood · 2025-11-03

  articleOpen access

  Abstract Introduction Pivotal trials that led to the approval of autologous anti-CD19 CAR T-cell therapy (CART) either excluded patients with prior CD19-directed therapy or required CD19 expression. Therefore, the activity of anti-CD19 CART in patients with CD19-negative lymphoma remains unknown. While due to practice heterogeneity and technical sensitivity, accurate detection of CD19 expression by immunohistochemistry (IHC) or flow cytometry may be limited, these are the only two assays clinically available. As CD19-negative large B-cell lymphoma (LBCL) cases are becoming increasingly frequent, we present the first retrospective multi-center real world experience using CART in patients with CD19-negative LBCL. Method Retrospective data from the Cell Therapy Consortium were utilized for this analysis. LBCL patients treated with autologous anti-CD19 CART in second line and beyond between April 2016 and June 2021, and with available CD19 expression status by either IHC or flow cytometry, were included in this study. Patients who had received prior CD19-directed therapy were excluded. Baseline characteristics prior to the initiation of lymphodepleting chemotherapy were collected. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy guidelines, and response was assessed by investigator according to the Lugano 2014 criteria. Chi-square test or Fisher's exact test was used to evaluate the association between baseline categorical characteristics and CD19 expression, while Wilcoxon rank sum test was used to evaluate the difference in continuous variables between CD19 expression groups. Log-rank test was used to compare the differences in progression-free survival (PFS) or overall survival (OS) between/among patient groups. Results Among 211 LBCL patients, 81 (38.4%) had CD19 status available by IHC, 193 (91.5%) by flow cytometry, and 63 (29.9%) by both. Of interest, no patient who received CART in the second line had CD19 status available, and all patients included in the analysis had received CART in the third line and beyond. Overall, 37 patients (17.5%) were CD19-negative before CAR T-cell therapy by either test. No significant differences in baseline characteristics were observed when comparing CD19-negative to CD19-positive cases, including age, sex, histology, product type, performance status, international prognostic index, refractory status, history of autologous or allogenic stem cell transplant, bridging therapy, and prior lines of treatment, except for a significantly lower median hemoglobin in CD19-positive patients (10.6 vs. 12.0 g/dL, p = 0.0054). CD19-negative patients experienced a 2-fold lower incidence of ICANS of any grade (21.6% vs. 43.1%, p = 0.0151) and over 5-fold lower G3-5 ICANS (5.4% vs. 28.7%, p = 0.0015). No significant differences in CRS of any grade (67.6% vs. 73.0%, p = 0.50), G3-4 CRS (5.4% vs. 8.0%, p = 0.74), and day-30 G3-4 cytopenia (40.0% vs. 54.0%, p = 0.24) were observed when comparing the two groups. At day-90 assessment, no difference in overall response rate (51.7% vs. 60.0%, p = 0.41) or complete response rate (37.9% vs. 51.1%, p = 0.20) was observed when comparing CD19-negative to CD19-positive patients. With a median follow up of 18.7 months (95% confidence interval 14.4 – 21.5), no significant difference in PFS (median 3.48 vs. 7.33 months, estimated 2-year 30.1% vs. 30.6%, p = 0.55) or OS (median 22.3 vs. 13.7 months, estimated 2-year 45.7% vs. 44.4%, p = 0.84) was observed when comparing the two groups. Conclusion Our large real-world experience shows that, when using IHC or flow cytometry for CD19 expression assessment, patients with CD19-negative LBCL experience lower ICANS rates with anti-CD19 CART, potentially due to lower CD19 density, but overall efficacy is comparable to what is observed in CD19-positive LBCL. While our results support the use of anti-CD19 CART in CD19-negative LBCL, future larger studies with more sensitive CD19 testing than IHC and/or flow cytometry are warranted.

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• Frontline experience with second generation covalent Bruton tyrosine kinase inhibitors for mantle cell lymphoma: A single center experience

  Blood · 2025-11-03

  article

  Abstract Introduction: Mantle cell lymphoma (MCL) is usually an incurable lymphoma with no standard frontline therapy. Increasingly, Bruton tyrosine kinase inhibitors are utilized in frontline therapy, especially in older patients, but data remain limited in younger patients. We report our experience with a cohort of patients with MCL who received frontline second-generation BTKi +/- rituximab. Methods: We reviewed all patients treated at our institution with either acalabrutinib or zanubrutinib (BTKi) +/- maintenance rituximab who had therapy initiated by July 10, 2024. Adverse events (AEs) were graded based on CTCAE v5. We defined patients as either younger or older: patients <65 years old were considered younger unless noted to be autologous hematopoietic stem cell transplant (ASCT) ineligible. Patients ≥70 years were considered older. Patients aged 65-70 were assessed for ASCT eligibility; ASCT-ineligible patients were considered older. A cohort of patients who had frontline standard-of-care chemotherapy (R-HyperCVAD or R-CHOP/R-DHAP) was also collected for comparison to the younger BTKi-treated cohort. Results: Thirty patients received frontline second-generation BTKi. Eleven (37%) were younger and 19 (63%) were older. Twenty-three patients (77%) received acalabrutinib (10 with rituximab maintenance) and 7 patients (23%) received zanubrutinib (4 with rituximab maintenance). Twenty (67%) were male, 27 (90%) were white, and 3 (10%) were black. Median age was 70.9 years (range 44.8-93.4). Twenty-five (83%) had ECOG performance status (PS) 0-1. Twenty-seven patients had advanced stage disease (90%). MIPIb was high risk in 21 (70%); Ki-67 was ≥ 50% in 6/26 (23%) and ≥ 30% in 12/26 (46%). Three (10%) patients had blastoid MCL. Five of 26 (19%) patients had a TP53 aberration. Between younger and older cohorts, there were no significant differences in sex, ECOG PS, blastoid MCL, or presence of TP53 aberrations. MIPIb was significantly higher in older patients (6.3 vs. 7.2, p=0.003). Overall, 24 patients (80%) had an AE related to BTKi, with 7 (23%) experiencing a serious AE (SAE). The most common AEs were bleeding/bruising (33%), infections (n=8, 27%; 1 URI, 4 pneumonia, 1 bacteremia, 1 urinary tract infection, 1 cellulitis; 3 were SAEs), and rash (20.0%). There was no significant difference between rate of any AE or SAE between older and younger patients. Five patients discontinued BTKi due to toxicity (recurrent neutropenia, rash, cellulitis, pneumonitis, dysgeusia) and one due to patient preference. Thirty-two patients were included in the frontline chemotherapy cohort. Twenty-five patients (78.1%) were male, 29 (90.6%) were white, two (6.3%) were black, and one (3.1%) was Hispanic. Median age was 60.3 years (range 27.3-74.5 years). Twenty-eight (87.5%) patients had an ECOG PS 0-1. Median stage was 4 (range 2-4) and median MIPIb was 6.8 (range 5.4-9.6). Nineteen (59.4%) of patients had classical MCL and 13 (40.6%) had blastoid/pleomorphic MCL. Five of 28 (18%) patients had a TP53 aberration. Comparing younger patients who received frontline BTKi and younger patients who received frontline chemotherapy, there were no significant differences in sex, ECOG PS, MIPIb, or presence of TP53 aberrations or proportion of patients who received maintenance rituximab; however, the younger BTKi cohort did have a significantly lower incidence of blastoid MCL (10% vs. 37%, p=0.02). Median follow-up for the entire cohort (n=62) was 58 months; estimated 3-year PFS for the BTKi (n=30) and chemotherapy cohorts (n=32) was 57% (95%CI 34-74%) vs. 43% (95%CI 26-60%). Median follow-up for the younger BTKi and younger chemotherapy cohorts was 35 and 102 months, respectively. Estimated 3-year PFS for the younger BTKi cohort (n=11) vs. younger chemotherapy cohort (n=27) was 52% (95%CI 20-77%) vs. 48% (95%CI 25-61%). Conclusions: Second-generation BTKi with and without rituximab appear safe and effective frontline therapy for MCL regardless of patient age. We also observed excellent BTKi outcomes in younger patients comparable to standard-of-care chemotherapy. Limitations include a higher proportion of patients in the frontline chemotherapy group with blastoid MCL as well as relatively short follow-up in the BTKi cohort. Nevertheless, second generation BTKi may represent an effective frontline therapeutic approach for patients with MCL. Further studies are needed to determine the role of chemotherapy with BTKi vs chemotherapy-free regimens in this setting.

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• Fixed treatment duration mosunetuzumab continues to demonstrate clinically meaningful outcomes in patients with relapsed/refractory (R/R) follicular lymphoma (FL) after ≥2 prior therapies: 5-year follow-up of a pivotal Phase II study

  Blood · 2025-11-03

  articleOpen access

  Abstract Background: Mosunetuzumab is the first FDA- and EMA-approved CD20xCD3 T-cell engaging bispecific antibody for the treatment of R/R FL after ≥2 prior lines of therapy. In a pivotal Phase II study (NCT02500407), fixed-duration mosunetuzumab demonstrated high response rates, durable remissions, and a manageable safety profile in patients with R/R FL (Budde et al. Lancet Oncol 2022; Shadman et al. ASH 2024; Cheah et al. EHA 2025). We report updated efficacy and safety data for mosunetuzumab in patients with R/R FL after a median follow-up of 5 years. Methods: Eligible patients with R/R FL Grade 1–3a and ≥2 prior therapies received intravenous mosunetuzumab for a fixed duration with step-up dosing in Cycle (C)1. Hospitalization was not mandatory. Patients with a complete response (CR) by C8 completed therapy with no additional cycles; patients with partial response or stable disease post C8 could continue treatment for up to 9 additional cycles (a total of 17 cycles). Efficacy analyses by investigator assessment (Cheson et al. 2007 criteria) included CR rate, overall response rate (ORR), duration of response (DOR), duration of CR (DOCR), progression-free survival (PFS), overall survival (OS) and time to next treatment (TTNT). Safety and tolerability were assessed by describing the incidence and severity of adverse events (AEs). After the AE reporting period (90 days after the last dose or start of new anti-lymphoma treatment), mosunetuzumab-related serious AEs were to be reported. Results: Ninety patients with R/R FL were enrolled, of whom 52% had a history of disease progression within 24 months from the start of first-line therapy (POD24) and 53% were double refractory. Median age was 60 years (range: 29–90) and median prior lines of therapy was 3 (range: 2–10). As of May 1, 2025, median time on study was 60.2 months (range: 2–72). In the overall population (N=90), the ORR and CR rate were 78% and 60%, respectively; median DOR (n=70) was 46.4 months (95% confidence interval [CI]: 18.7–not estimable [NE]), and median DOCR (n=54) was not reached (95% CI: 44.1–NE). The 54-month DOR and DOCR rates were 46% (95% CI: 33.8–59.1) and 52% (95% CI: 36.2–67.9), respectively. Median PFS was 24.0 months (95% CI: 12.0–53.2) in all patients, and 61.0 months (95% CI: 47.6–NE) in patients who achieved CR. The 5-year PFS rates were 36% (95% CI: 25.3–47.7) and 57% (95% CI: 42.0–71.6) in all patients and patients with CR, respectively. Median OS was not reached (95% CI: NE), and the 5-year OS rate was 78% (95% CI: 69.6–87.4). Eighteen deaths were reported; 13 due to progressive disease, 1 each due to unexplained death, cardiac arrest and sepsis, and 2 with unknown cause. The median TTNT in all patients was 64.1 months (95% CI: 21.7–NE), and the 5-year TTNT rate was 51% (95% CI: 39.8–61.8). Five patients received mosunetuzumab retreatment of whom 3 achieved a subsequent CR. In the 47 patients with POD24, the ORR (81%) and CR rate (60%) were consistent with those observed in the overall population. Median DOCR was 50.1 months (95% CI: 18.7–NE), and the 54-month DOCR rate was 48% (95% CI: 24.9–71.5); median PFS was 21.7 months (95% CI: 11.6–61.0) and the 5-year PFS rate was 36.9% (95% CI: 20.7–53.1), with a small number of patients remaining at risk. No new AEs were reported since the 4-year follow-up. All patients had at least one AE; the most common AE was cytokine release syndrome (CRS; 44%). CRS events were mainly Grade 1/2 (Grade 1, n=23; Grade 2, n=15; Grade 3, n=1; Grade 4, n=1) and were all resolved. AEs leading to treatment discontinuation occurred in 4% of patients; no treatment-related Grade 5 AEs occurred. The recovery of B cells and immunoglobulin M (IgM) was observed in patients with a CR. Conclusions: This report represents the longest follow-up for a CD20xCD3 bispecific antibody in R/R FL. Fixed-duration mosunetuzumab treatment yields durable responses, and long-term survival continues to be observed in patients with heavily pre-treated R/R FL. The data highlight the durable long-term remissions achieved with mosunetuzumab in this setting. Updated data confirm that B-cell recovery is observed and sustained. In parallel, IgM levels recover with a similar time course. In both cases after 2 years a majority of patients have recovered to normal levels. The safety profile remained manageable, with no new toxicities reported.

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• Cardiovascular outcomes of patients transitioned from ibrutinib to an alternate bruton tyrosine kinase inhibitor for hypertension and/or cardiovascular adverse events

  Blood · 2025-11-03

  articleSenior author

  Abstract Introduction: Bruton tyrosine kinase inhibitors (BTKi) are highly efficacious oral agents FDA-approved for treatment of specific B-cell malignancies. BTKi are generally administered until disease progression, intolerable toxicity, or death. The emergence of cardiovascular adverse events (CVAE) including hypertension (HTN), arrhythmias, heart failure, and sudden death have limited the use of ibrutinib (Ibr), the first-in-class BTKi FDA-approved in 2013. Hypertension (HTN) is a frequent and cumulative toxicity of Ibr that is associated with increased risk of major adverse cardiac events. Alternate covalent BTKi (acalabrutinib, zanubrutinib) and non-covalent BTKi (pirtobrutinib) have lower rates of CVAE in clinical trials compared with Ibr. The objective of this study was to analyze the real-world incidence of HTN and CVAE in patients (pts) on Ibr and the outcome of pts with new or worsening HTN on Ibr who were then transitioned to an alternate BTKi. Methods: We conducted a retrospective electronic medical record review of pts with hematologic malignancies treated with Ibr from January 2013 to July 2024 at the University of Pennsylvania. Blood pressure (BP), cardiovascular medications, comorbidities, and CVAE were analyzed prior to Ibr (baseline), while on Ibr, and while on subsequent BTKi (acalabrutinib, zanubrutinib, or pirtobrutinib). Eligible pts had at least 3 BP measurements available during each of the following periods: 1) within 12 months of Ibr initiation; 2) while on Ibr; and 3) while on subsequent BTKi. All available BP values were used to calculate medians and means for each therapy period. HTN was defined as elevated systolic BP (SBP) ≥130 and/or diastolic BP (DBP) ≥80 on more than one occasion with physician confirmation of the diagnosis. Worsening HTN was defined as pts with antecedent HTN with an increase in the number or doses of prescribed antihypertensives. Graphpad/R 4.4.0 were used for statistical analysis. Results: A total of 114 pts received Ibr for 408.7 patient-years and 77 (68%) of pts had CLL. The median age was 67 (range 27-86) and 81 (71%) pts were men. On Ibr, 109 (96%) pts had systolic HTN and 100 (88%) had diastolic HTN. Across all BTKi, 74 (65%) pts had a CVAE. CVAE led to Ibr discontinuation in 58 (51.5%) pts, including HTN (n = 20, 18%), atrial fibrillation (n = 25, 22%), other arrhythmia (n = 1, 0.9%), palpitations (n = 2, 1.8%) and hemorrhage (n = 10, 8.8%). Among all pts on Ibr, 67 (59%) had either new onset HTN (n = 49, 43%) or developed worsening HTN with an increase in anti-HTN medications (n = 18, 16%). The median time on Ibr to first elevated SBP and maximum SBP were 32 (95% CI: 24 – 49) and 342 (95% CI: 229 – 604) days, respectively. The median time on Ibr to first elevated DBP and maximum DBP were 114 (95% CI: 83 –199) and 335 (95% CI: 250 – 465) days, respectively. Among the 109 pts with HTN on Ibr, transition to acalabrutinib (n = 67, 61%) or zanubrutinib (n = 33, 20%) resulted in a mean reduction in SBP of -9 mm/Hg (95%CI: -13 to -5.1) and -6 mm/Hg (95%CI: -11 to -0.8), respectively, without a change in number of antihypertensive medications. There were no observed differences in SBP, DBP, or the number of anti-HTN medications among pts with HTN on Ibr who transitioned to pirtobrutinib (n = 9, 8%). Among pts with HTN on Ibr, 45 (41.3%) had resolution of HTN with a median time to resolution (mTTR) of 2,277 days (95% CI: 1,996 – 2,463), although this time estimate is biased by infrequent follow-up. Among 55 pts with documented HTN on Ibr who transitioned to acalabrutinib, 20 (36.4%) had resolution of HTN with mTTR of 1,463 days (95% CI: 976 – NE). Among pts with documented HTN on Ibr who transitioned to zanubrutinib (n = 26) and pirtobrutinib (n = 8), HTN resolved in 8 (30.8%) and 2 (25%) with mTTRs of 683 (95%CI: 606 – NE) and NR (95%CI: 158 – NE) days, respectively. Conclusion: BTKi are associated with increased risk of CVAE; 43% of pts on Ibr developed new onset HTN and 52% of pts discontinued Ibr due to a CVAE. Among pts with HTN on Ibr, transition to alternate covalent BTKi was associated with a reduction in mean SBP as well as resolution of HTN, in some patients, without an increase in number or dose of antihypertensive medications. Despite the development of HTN on Ibr, BP can improve after replacing Ibr with an alternate BTKi.

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• Deep learning-based image analysis of pretreatment FDG-PET/CT predicts CAR-T cell treatment outcome at month-12 for patients with Relapsed/Refractory large B-cell lymphomas

  Blood · 2025-11-03

  articleOpen access1st authorCorresponding

  Abstract Introduction: We previouslyreportedthe feasibility of predicting treatment outcome of chimeric antigen receptor modified T-cell (CAR-T) therapy for patients (pts) with relapsed or refractory large B-cell lymphomas (r/r LBCL) from pretreatment diagnostic imaging studies. This method used deep-learning (DL)-based image analysis for lesion-level response prediction and estimated patient-level outcomes from lesion-level predictions by rule-based reasoning (Tong Y, et al. PLoS ONE 2023;18(7):e0282573). To further test the prognostic validity of this method, we analyzed baseline (pre-CAR-T infusion) FDG-PET (PET) and low-dose CT (LD-CT) images performed as part of the JULIET trial with investigators blinded to pt treatment outcomes. The JULIET trial is a phase 2 study of tisagenlecleucel, a CD19-directed CAR-T therapy, in adult pts with r/r LBCL (NCT02445248). Here, we compare this approach with serum LDH and secondary International Prognostic Index (sIPI), which are generally accepted prognostic markers for LBCL treatment outcome. Methods: Pre-infusion imagesfrom 102 adult pts with r/r LBCL who were treated with tisagenlecleucel were evaluated. Image sets came from 27 hospitals in 10 countries and were acquired on 15 different model scanners from 3 leading manufacturers of diagnostic imaging equipment; 36 (35%) pt image sets were excluded from DL-based image analysis: 31 (30%) due to image low quality (26 LD-CT; 4 LD-CT+PET; 1 PET), 1 without nodal lesion, and 4 without metabolic confirmation of Month-12 response. Data from 3 contiguous whole-image slices through the mid-portions of nodal lesions on both PET and LD-CT images from each of the 66 pt image sets were analyzed using the previously described DL lesion-level model, without retraining, to predict treatment outcome. After analyzing image sets to generate predictions of outcome for each of the 66 evaluable pts, actual Month-12 pt outcomes were unblinded and grouped using protocol-specified radiologic response criteria as a Responder (met protocol-defined radiologic complete response [CR]) or a Non-responder (met protocol-defined radiologic partial response, stable disease or progressive disease [< CR]) at 12 months post CAR-T infusion. Actual Month-12 pt outcomes post-treatment (verified Responders, n = 13 [i.e., 20% CR]; verified Non-responders, n = 53 [i.e., 80% < CR]) were then compared with predictions obtained in blinded fashion from DL-based image analyses using 70% rule-based reasoning (i.e., if > 70% of lesions were predicted to respond by DL image analysis, the pt was predicted to be a Responder at Month-12; if < 70% lesions were predicted to respond, the pt was predicted to be a Non-responder at Month-12). Results: For 66 evaluable pts, DL-based prediction of Responder (CR) status as the outcome at Month-12 had a sensitivity of 77% (correctly identified Responders) with specificity 51% and balanced accuracy 64% (balanced accuracy reported because of imbalance between number of Responders and non-Responders). For comparison, serum LDH and sIPI score at enrollment were also evaluated as prognostic indices for 64 pts (2/66 pts excluded for missing LDH). Using serum LDH < 2 x upper limit of normal (ULN) to predict the outcome at Month-12 as Responder, sensitivity was 100% but specificity only 12% due to a high false positive rate; using LDH > 2 x ULN to predict outcome as Non-responder, sensitivity was only 12% (high false negative rate) with specificity 100%. Using sIPI > 2 to predict outcome as Non-responder at 12 months, sensitivity was 65% and specificity 62%. Conclusions: Prediction of CAR-T treatment outcome from pretreatment images using DL-based image analysis for lesion-level response prediction and rule-based reasoning for patient-level response estimation is feasible. Considering the challenges stemming from data heterogeneity and the small number of pts in this study, this approach showed a generalizable performance with the accuracy of patient-level predictions similar to earlier results obtained from our single center study. With continued refinement and addition of clinical covariates, this approach has the potential to provide clinically useful information in advance of CAR-T therapy.

  PublisherOA PDFDOI

• A newly identified role for IL-5 in regulating CART-associated toxicity and efficacy

  Blood · 2025-11-03

  article

  Abstract Background: CD19-directed CART cell (CART19) therapy has transformed the treatment of B-cell malignancies but is limited by life-threatening toxicities, including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), as well as low durable remission rates. Our understanding of the pathogenesis of CART-associated toxicities is limited, and although current treatments are effective, refractory cases remain challenging. Methods and Results: To investigate CRS/ICANS pathogenesis and identify new therapeutic targets, we analyzed plasma cytokine kinetics within the first month of CART19 cell therapy in 25 relapsed/refractory (r/r) large B-cell lymphoma (LBCL) and 14 r/r follicular lymphoma (FL) patients (NCT02030834). In this cohort, 22 (88%) patients developed any-grade CRS (73% LBCL, 27% FL) and 4 (16%) developed any-grade ICANS (50% LBCL, 50% FL). Across 30 analyzed cytokines, IL-5 emerged as the second most enriched cytokine based on the median peak-to-baseline (Day 0) ratio in patients who experienced CRS vs. those who did not. The IL-5 ratio was 6.6-fold higher (p<0.05) and 11.9-fold higher (p=0.093) in patients who experienced CRS or ICANS, respectively. Moreover, IL-5 was elevated in patients experiencing CRS on Days 1 and 2 (p<0.05). Prompted by our results, we evaluated the effect of IL-5 neutralization with a monoclonal antibody (mAb) on CART-associated toxicity in a patient-derived B-acute lymphoblastic leukemia (B-ALL) xenograft model. After engraftment (average of 110 human CD19+ cells/µL peripheral blood), NSG mice were randomized based on tumor burden and treated with 3.5×10⁶ CART19 plus either IL-5 mAb or IgG control (10 mg/kg, weekly), or no treatment. Mice receiving IL-5 mAb showed reduced weight loss (p<0.005, Days 13–16) and neuroscore (p<0.05, Day 15), as assessed by a daily, blinded 18-point assessment, vs. the IgG group. Additionally, while CRS-associated cytokines (GM-CSF, IFN-γ, MIP-1β) were significantly elevated in the IgG group (p<0.05) vs. the untreated group, they were not in the IL-5 mAb group. In this model, all mice treated with CART19 cells were able to clear the tumor burden. However, in a follow-up challenge model generated by engrafting NSG mice with 1x106 luciferase+ JeKo-1 cells, mice treated with a combination of 1x106CART19 cells + IL-5 mAb showed reduced weight loss (p<0.0001) and enhanced overall survival (p<0.01) vs. mice treated with CART19 + IgG. Next, we evaluated IL-5 neutralization in an immunocompetent toxicity model. BALB/c mice were treated with 10×10⁶ murine untransduced T cells, CART19 + IL-5 mAb, or CART19 + IgG (10 mg/kg, weekly). Mice receiving IL-5 mAb exhibited significantly reduced weight loss (p<0.05, Day 1) and lower neuroscore (p<0.05, Days 1, 6, and 8) vs. those receiving IgG control, with a consistent trend observed on other days, supporting a protective role for IL-5 blockade in mitigating CART-associated toxicities. To explore the direct effects of IL-5 on CART19 cells, we disrupted either IL-5 (IL-5KO-CART19) or its receptor (IL-5RαKO-CART19) using CRISPR-Cas9. In NSG mice engrafted with 1×10⁶ luciferase+NALM6 cells, mice receiving 1×10⁶ IL-5KO-CART19 vs. IL-5WT-CART19 showed a trend toward reduced weight loss (p=0.08), significantly increased antitumor activity by Day 20 (p<0.05), and improved overall survival (p<0.05), indicating that IL-5 production can significantly impair CART19 cell efficacy. We next evaluated changes in IL-5Rα gRNA representation in a published genome-wide CRISPR screen (PMID: 39266501). CART19 cells with IL-5Rα-targeting gRNAs were enriched following chronic stimulation, indicating a protective effect for IL-5 pathway interruption. In subsequent studies, IL-5RαKO-CART19 cells showed enhanced killing of JeKo-1 cells following 48 hours of co-culture (p<0.05) and reduced co-expression of multiple inhibitory markers (p<0.01) following chronic stimulation with JeKo-1 cells for one week vs. IL-5RαWT-CART19 cells, suggesting an improvement in CART19 cell activity and phenotype following disruption of IL-5Rα. Conclusion: Our data identify IL-5 as a previously unrecognized mediator of CART–associated toxicities and show significant improvement of CART19 activity with disruption of IL-5 signaling either indirectly with an IL-5 neutralizing antibody or directly with CRISPR gene editing. Thus, IL-5 could serve as a dual-purpose target to improve both safety and efficacy of CART cell therapy.

  PublisherDOI

• Patient-reported outcomes (PROs) with lisocabtagene maraleucel (liso-cel) in patients with third line or later (3L+) R/R MZL from the Phase 2 TRANSCEND FL study

  Blood · 2025-11-03

  articleOpen access

  Abstract Introduction: The CAR T cell therapy liso-cel showed promising efficacy and safety in patients with 3L+ R/R MZL in TRANSCEND FL (NCT04245839), a global, phase 2, open-label, single-arm, multicohort, pivotal study (Palomba ML, et al. Hematol Oncol 2025). Here, we present corresponding data for PROs. Methods: Adults with R/R MZL after ≥2 prior lines of therapy (3L+), including those previously treated with a combination of an anti-CD20 antibody and alkylating agent, or who had relapsed disease after HSCT, were enrolled. After leukapheresis, lymphodepleting chemotherapy (LDC), and optional bridging therapy, patients received 1 infusion of liso-cel (100×106 CAR+ T cells). Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-30 items (EORTC QLQ-C30), Functional Assessment of Cancer Therapy-Lymphoma “Additional Concerns” Subscale (FACT-LymS), and EQ-5D-5L on the following schedule: pretreatment (≤7 days before LDC; baseline); before infusion on day of liso-cel infusion (Day 1); on Days 15 and 29, and Months 2, 3, 6, 9, 12, 18, and 24 after infusion; and at end of study assessment. Results focus on 8 key PRO scales: 6 primary domains from the EORTC QLQ-C30 (global health status/quality of life [QOL], physical functioning, role functioning, cognitive functioning, fatigue, and pain), the FACT-LymS subscale assessing lymphoma-specific symptoms, and the EQ-5D-5L visual analog score (VAS). Unless otherwise stated, analyses were performed in all liso-cel–treated patients with assessments at baseline and ≥1 postbaseline visit. Linear mixed-effects models for repeated measures were used to calculate least squares (LS) mean change from baseline to Month 18 visit, with responses available for ≥30 patients. The proportion of patients with clinically meaningful changes from baseline were summarized using published thresholds for “meaningful within-patient change.” Time to confirmed improvement in PROs was assessed in all PRO-evaluable liso-cel–treated patients who had potential for meaningful within-patient change as assessed by the Kaplan-Meier method. Results: Among 67 liso-cel–treated patients with 3L+ R/R MZL, 60 were evaluable for EORTC QLQ-C30 analysis (median age, 63 years; 57% male; 55% White). Disease subtypes included extranodal (23%), nodal (48%), and splenic (28%) MZL. Assessment completion rates were >80% across visits up to Month 18 visit. At baseline, mean scores across primary EORTC QLQ-C30 domains were comparable to or slightly above general population norms in Europe and the US. LS mean changes from baseline showed an initial deterioration in EORTC QLQ-C30 primary domains between Day 1 and Day 15, followed by improvements between Day 15 and Month 2 in 5 domains (all except cognitive functioning, which remained stable throughout, reflecting consistently higher scores than the mean general population norms in Europe and the US). These improvements were generally maintained or further enhanced beyond Month 3, with mean scores at Month 18 remaining above baseline values. Additionally, 4 primary domains (global health status/QOL, physical functioning, role functioning, and fatigue) exceeded the threshold for clinically meaningful improvement. Patients demonstrated improvement in lymphoma specific symptoms as assessed by FACT-LymS starting at Day 15, reaching clinically meaningful improvement by Month 2 and remaining improved through Month 18. Patients showed improvement in the EQ-5D-5L VAS as early as Day 15 reaching the minimum threshold to be considered clinically meaningful at Month 6 and remaining improved through Month 12. Across all PROs, the majority of patients (58%–94%, depending on domain and visit) experienced either improvement or no change in primary domains from Day 29 onward. Median time to confirmed improvement was within 4 months for EORTC QLQ-C30 domains and FACT-LymS. Conclusions: In TRANSCEND FL, most patients with 3L+ R/R MZL experienced clinically meaningful improvements in PROs after liso-cel treatment, including symptom relief, enhanced functioning, and improved QOL. The study represents one of the biggest efforts to characterize PROs in patients with 3L+ R/R MZL and provides valuable insights into the patient experience following treatment with liso-cel. The PRO results complement the clinical efficacy and safety profile of liso-cel in 3L+ R/R MZL, reinforcing its potential to become standard of care in this setting.

  PublisherOA PDFDOI

Recent grants

• NIH Grant K08HL002167

  NIH · $358k · 1995

Frequent coauthors

• Sunita D. Nasta

  University of Pennsylvania

  604 shared

• Jakub Svoboda

  University of Pennsylvania

  540 shared

• Elise A. Chong

  Hospital of the University of Pennsylvania

  477 shared

• Daniel J. Landsburg

  407 shared

• Charalambos Andreadis

  University of California, San Francisco

  237 shared

• Stefan K. Barta

  225 shared

• Anthony R. Mato

  220 shared

• Marco Ruella

  University of Pennsylvania

  188 shared

Education

• MD

  Thomas Jefferson University Hospitals

• Medical Oncology Fellowship

  Pennsylvania Hospital

  1989

• Postdoctoral Research Fellowship (NIH Sponsored Individual NRSA), Cardeza Foundation for Hematologic Research

  Thomas Jefferson University Hospitals

  1988

• Cardeza Clinical and Research Fellow in Medicine (Hematology)

  Thomas Jefferson University Hospitals

  1988

• Medical Internship

  Pennsylvania Hospital

  1982

• B.S. Psychology

  Saint Joseph's University

  1976