Jakub Svoboda
VerifiedUniversity of Pennsylvania · Rehabilitation Medicine
Active 1949–2025
About
Jakub Svoboda, MD, is an Associate Professor of Medicine (Hematology-Oncology) at the Hospital of the University of Pennsylvania. His research interests focus on improving outcomes in patients with lymphomas through the use of novel agents and immune-based therapies. He has been involved in clinical trials utilizing chimeric antigen receptor (CAR) T cells, including a first-in-human trial using armored CAR T cells that secrete interleukin 18 to enhance their activity and expansion. Dr. Svoboda serves as the principal investigator of this trial and collaborates with translational scientists to identify new therapeutic targets for cellular therapies. Clinically, he has expertise in treating all subtypes of lymphomas and CLL/SLL. His contributions include co-chairing conferences on hematologic malignancies and participating in multidisciplinary tumor boards. His work combines clinical practice with innovative research aimed at advancing immunotherapy and targeted treatments for lymphoma patients.
Research topics
- Medicine
- Internal medicine
- Oncology
- Immunology
- Cancer research
- Pathology
- Family medicine
Selected publications
International Journal of Radiation Oncology*Biology*Physics · 2025-09-01
articleOpen accessBlood · 2025-11-03
articleOpen accessAbstract Background Previous work has linked the inferior prognosis of patients with newly diagnosed large B cell lymphoma (LBCL) of activated B cell (ABC) cell of origin (COO) by gene expression profiling (GEP) with both double expressor (DE) features (PMID 23449635) and MCD genetic subtype (PMID 32289277 and 34739844). However, it is unknown whether these findings apply to LBCL tumors diagnosed in routine clinical practice, for which COO is typically assigned by immunohistochemistry (IHC) and genetic subtype based upon targeted next generation sequencing (NGS) panels. Methods We retrospectively compiled patients with newly diagnosed LBCL from multiple data sets (PMID 32780847, 30523716, and Hematological Oncology, 43: e180_70094). Inclusion criteria were cases with non-GCB COO by Hans algorithm, treatment with R-CHOP, known DE status (cutoffs MYC IHC ≥40% and BCL2 IHC ≥50%), known MYC rearrangement (MYC-R) status, calculable International Prognostic Index (IPI) score of <3 vs ≥3, available NGS data, and >12 months of follow-up without evidence of disease progression. MCD-like subtype by LymphPlex (PMID 37032379) and MYD88 subtype (PMID 34378195) were assigned based upon available variant data. Results Of 689 total cases, 218 met inclusion criteria and were analyzed. Baseline characteristics included IPI score ≥3 46%, MYC-R 6%, DE 43%, TP53 mutation 24%, any MYD88 mutation 31%, MYD88 L265P mutation 22%, PIM1 mutation 33%, ETV6 mutation 14% (tested in 83 cases), TBL1XR1 mutation 16% (tested in 83 cases), MCD-like subtype 16%, and MYD88 subtype 22%. Of note, for 138 cases for which COO was also reported by Lymph2Cx, 72% were assigned ABC, 9% GCB, and 19% unclassified. DE was associated with the presence of MYC-R (p=0.046), MCD-like subtype (p=0.09), and MYD88 subtype (p=0.02), but no other baseline characteristic. As was the case for DE, neither MCD-like nor MYD88 subtype were associated with IPI score. Neither MCD-like nor MYD88 subtype was associated with MYC-R, and MYD88 subtype was not associated with TP53 mutation (noting cases with TP53 mutation were assigned to an independent cohort by LymphPlex). For the entire cohort, with a median length of follow-up was 70 months (range 37-123 months across cohorts), the 3-year progression-free survival (3yPFS) was 65% (95% confidence interval [CI] 58-71%) and estimated 3-year overall survival (3yOS) was 71% (95% CI 64-77%). Inferior 3y PFS was associated with IPI score ≥3 (p<0.001), MYC-R (p=0.008), DE (p=0.002), TP53 mutation (p=0.07), MYD88 mutation (p=0.02), and MYD88 L265P mutation (p=0.004) by univariate analysis (UVA) with significance level p<0.10; however, only IPI score ≥3 (hazard ratio [HR] 2.2, 95% CI 1.4-3.5, p=0.001) and DE (HR 1.9, 95% CI 1.2-3.0, p=0.007) remained significant on multivariate analysis (MVA) with significance level p<0.05. On UVA, inferior 3yOS was associated with IPI score ≥3 (p<0.001), MYC-R (p=0.001), and DE (p<0.001), with all remaining significant on MVA: IPI score ≥3 (HR 3.1, 95% CI 1.8-5.4, p<0.001), DE (HR 2.3, 95% CI 1.4-3.9, p=0.002), and MYC-R (HR 2.3, 95% CI 1.1-5.0, p=0.03). For patients with vs without DE, 3yPFS was 53% (95% CI 42-62%) vs 74% (95% CI 65-81%) (p=0.001) and 3yOS 57% (95% CI 47-67%) vs 81% (95% CI 77-87%) (p<0.001). Finally, one cohort (PMID 30523716) reported genetic classification by LymphGen, in which 16% of cases were classified as MCD genetic subtype. Subgroup analysis of this cohort (n=122) revealed an association between DE and MCD genetic subtype by LymphGen (p<0.001). Additionally, MCD genetic subtype by LymphGen was associated with inferior 3yPFS on UVA (p=0.06), but not MVA (HR 1.4, 95% CI 0.7-2.7, p=0.32) when incorporating IPI score and DE, both of which remained significant. MCD genetic subtype by LymphGen was not significantly associated with 3yOS on UVA (p=0.20). Conclusions DE is a biomarker of inferior 3yPFS and 3yOS independent of IPI score or genomic features analyzed in this multi-national cohort of newly diagnosed non-GCB LBCL patients. MCD genetic subtype as well as genetic subtypes approximating MCD are associated with DE but are not independently prognostic in this patient population. These findings have implications for non-GCB LBCL patients diagnosed in routine clinical practice, and support further exploration of common molecular features that predict for chemoresistance, as well as evaluation of the efficacy of targeted therapies, in newly diagnosed non-GCB DE LBCL patients.
Blood · 2025-11-03
articleAbstract 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.
Cancer Epidemiology Biomarkers & Prevention · 2025-09-18
articleAbstract Background: The incidence of classical Hodgkin lymphoma (CHL) varies by demographic factors including race/ethnicity and birthplace. For this study, we aimed to describe differences in demographic and clinical characteristics between US-born and non-US-born Latinos diagnosed with CHL overall in our study cohort. As age has a known association with histological subtype and other clinical characteristics in CHL, we further stratified by age and evaluated Adolescent and Young Adult (AYA) (15 to 39 years old at time of diagnosis) and older adults (40+ years old at time of diagnosis) separately Methods: For the (M)ulti (E)thnic (S)tudy of (H)odgkin Lymphoma (MESH) we collected formalin-fixed paraffin-embedded (FFPE) tumor blocks from 912 multiethnic cases of CHL from multiple sites, including cancer centers, hospitals, and Residual Tissue Repositories. Cases in our study cohort were diagnosed between 1986 and 2019. We utilized Fisher's exact test to assess statistical differences of categorical demographics and clinical characteristics between Latino cases with US and non-US birthplace in our cohort. Logistic regression models were used where the dependent variable was each binary "Characteristic" with independent variables: birthplace (nonUS-born vs US-born), age at diagnosis, and sex. Results: Three hundred fifty-eight cases (39.3%) were identified as Latino based on available records. We were able to confirm the country of birth for 202 (56.4%) of these cases, with 71 US-born and 131 nonUS-born Latinos. Among nonUS-born cases, 79% reported Mexico as their birthplace. The country of origin is representative of our local population. nonUS-born Latinos were older (p=<0.001 ) and had a higher prevalence of late stage disease at the time of diagnosis (p <0.001) than their US-born counterparts. nonUS-born Latinos were more likely to be of low socioeconomic status (SES) compared to US-born Latinos (P-value=0.003). We observed no significant differences in sex, first course of treatment, B symptoms, histology, or Epstein-Barr virus (EBV) tumor status between the two groups. Within AYA cases, we found a significant difference in stage with US-born Latinos having earlier stages at diagnosis (P-value <0.001) compared to Latin American-born AYA Latinos in our cohort. We also noted a trend towards Latin American- born Latinos having a lower SES (P-value=0.009). There were no significant differences in sex, first course of treatment, B symptoms, histology, or EBV status. These trends were also evident after adjusting for age and sex. Specifically, after adjusting for age and sex, there was a 7.24 and 4.83 times higher odds of having later stage (P=0.0002) and lower SES (P=0.01), respectively, among non-US-born compared to US born. Conclusions: We observed significant differences in age, stage at diagnosis, and socioeconomic status in cases by birthplace. Compared to US-Born AYA Latino patients, nonUS-born AYA Latino patients had a higher likelihood of having later stage and lower SES. Thus, targeting the disparities in this age group will be critical. Citation Format: Jose Alejandro. Aparicio, Jia Angel. Wan, Esther Lam, Mallory Bernstein, Sheeja T. Pullarkat, Deepthi Karunasiri, Anthony Colombo, Joo Song, Chun Chao, Brenda Hernandez, Tomohiro Aoki, Pamela B. Allen, Christopher R. Flowers, Sophia Wang, Juanita Evans, Owen Chen, Elva Jiménez Hernández, Juan Carlos Núñez Enríquez, José Arellano Galindo, María del Rosario Mora Campos, Susana Elizabeth Anaya Aguirre, David Scott, Megan Lim, Leon Bernal-Mizrachi, Jakub Svoboda, Christian Steidl, David Conti, Imran Siddiqi, Juan Manuel Mejia Arangure, Wendy Cozen. Clinical and demographic differences between children and young adult US-born and non-US-born Latinos diagnosed with classical Hodgkin Lymphoma in the MESH Study Cohort [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A091.
Blood · 2025-11-03
articleOpen accessAbstract Background. T-cell lymphomas carry a very poor prognosis and lack effective treatments. Despite the transformative success of chimeric antigen receptor (CAR) T-cell therapies in B-cell malignancies, translation to T-cell malignancies has been impeded by target antigen overlap that causes CAR T-cell fratricide and on-target T-cell aplasia. Senza5 CART5 is an autologous, gene-edited, dual-population, rapidly manufactured (5-day) CAR T-cell (CART) product comprised of both a CD5-deleted (CRISPR-Cas9) CAR-expressing (lentivirus transduced) T cell population (CD5⁻ CAR⁺) and a CD5-deleted, non-transduced T-cell population (CD5⁻ CAR⁻). This dual population is designed to enhance both potency and safety as CD5 deletion removes a negative regulator of T-cell effector function (Patel R., Science Immunology, 2024), while the companion CD5⁻ CAR⁻ cells are intended to mitigate on-target T-cell aplasia during immune reconstitution. Methods. In this open-label, dose-finding Phase 1 trial, adults with histologically confirmed relapsed/refractory (r/r) CD5+ T-cell lymphoma after ≥ 1 prior therapy receive lymphodepletion (fludarabine 25 mg/m² + cyclophosphamide 250 mg/m² x 3 days or bendamustine 90 mg/m² x 2 days) followed by a single IV infusion of Senza5 CART5 at doses ranging from 3x106 to 1.25x108 CAR+ cells. Primary endpoints are safety and recommended Phase 2 dose (RP2D); secondary/exploratory endpoints include manufacturing feasibility, in vivo expansion, tissue trafficking, T-cell aplasia mitigation, overall response rate (ORR), and complete response (CR) rate per Lugano criteria. The Viper 101 trial is ongoing (NCT06420089). Results. As of August 5, 2025, 6 patients were manufactured and 5 patients (pts) were treated (1 at a flat dose of 1x107 CAR+ cells and 4 at a flat dose of 3x106 CAR+ cells) with 4 pts evaluable for dose limiting toxicities (safety) and 3 pts evaluable for efficacy. Median age was 65 years (range 55–75); histologies included PTCL-NOS (n=2), TFHL (n=1), AITL (n=1), and MF (n=1). Pts had a median of 3 prior lines (range 2–5), and 2 had prior autologous stem cell transplant. Manufacturing success was 100% (6/6). Treatment-related adverse events (TRAEs) included cytokine-release syndrome (CRS) (Grade 1–2) in 100% of safety-evaluable pts (4/4) that resolved with standard care; no neurotoxicities or hemophagocytic lymphohistiocytosis syndrome were reported. All pts experienced Grade 3–4 transient cytopenias and Grade 1-2 TRAEs of the skin, mouth, and gastrointestinal tract. Infections were observed in 3/4 pts . One pt treated at the 1x107 CAR+ dose experienced a Grade 5 severe AE (infection) on Day 54 while presenting with multineage cytopenias that were considered unrelated to the investigational product. No pts experienced clinical EBV or CMV infections. All safety-evaluable pts (n=4) experienced robust in vivo CART cell expansion (median peak in peripheral blood (PB): 33,664 copies/µg gDNA). On-treatment biopsies confirmed CART trafficking to disease sites, including lymph nodes, skin, and marrow. Of note, no detectable CD5+ cells (normal or malignant) were detected in these biopsies. CART cells persisted and were still detected in the PB at last follow-up (median 1,426 copies/µg gDNA). Due to the risk of on-target T-cell toxicity, immune reconstitution was also monitored. By Day 28, all evaluable pts demonstrated reconstitution of a CD5-negative, CAR-negative (CD5- CAR-) T-cell compartment (both CD4+ and CD8+ subsets). Among efficacy-evaluable pts (n=3), overall response rate (ORR) was 100% (3/3) with all three pts achieving a complete response (CR) at a median follow-up of 4.0 months (range 1.9–5.5). 2/3 pts had FDG-avid lesions on the Day 30 scan, which, upon biopsy, were negative for the original lymphoma, and became PET negative by Day 90. No patients have relapsed at last follow up. Updated clinical outcomes and correlative data for all pts treated will be presented at the meeting. Conclusions. Early results suggest that Senza5 CART5 has manageable toxicities, potent antitumor activity, robust and durable CART expansion, and T-cell reconstitution at low doses of CART cells (3x106 CAR+ cells). While follow-up is limited, these data support further development of Senza5 CART5 for r/r T-cell lymphomas. Moreover, these results underscore the potential for CD5 deletion as a platform to broadly enhance the efficacy of engineered T-cell therapies for additional indications.
Blood · 2025-11-03
articleOpen accessAbstract 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.
Blood · 2025-11-03
articleOpen accessAbstract Chimeric antigen T-cell receptor (CART) therapy is highly effective for pts (pts) with relapsed/refractory (R/R) lymphoma/multiple myeloma (MM). However, due to concerns regarding tolerability, older pts are underrepresented in CART trials and real-world studies indicate that CART is underutilized in older adults. Methods to assess fitness for CART are ECOG, clinician gestalt and age. There is interest in improving risk stratification of older adults using objective measures. Fried's frailty phenotype (FP) uses subjective (exhaustion, reported weight loss, activity level) and objective (gait speed, grip strength) measures to categorize pts into fit, pre-frail, and frail. We have previously shown that FP predicts for overall survival (OS) in older stem cell transplant (SCT) recipients. We hypothesize that FP will be associated with progression-free survival (PFS) and OS in older pts with lymphoma/MM undergoing CART therapy. We prospectively enrolled pts ≥ 60 years planned for CART for R/R lymphoma/MM from May 2019 – 2023 on a clinical trial. We performed FP prior to CART infusion, and at 7 days (d), 14d, 21d, 1 month (mo), 3mo, 6mo and 12mo post-infusion. 36 pts were enrolled with a median age at CART infusion of 69 years (Range 60-81). 53% of pts had MM, of whom 63% had intermediate or high-risk disease by R-ISS. The remainder had lymphoma (diffuse large B-cell or follicular lymphoma) with IPI > 2 at diagnosis in 59%. Idecagtagene vicleucel and tisagenlecleucel were the most frequently administered CART products. Median follow up was 33mo. Median prior lines of therapy (LOT) was 3 (Range 1-7) and 47% had prior auto-SCT. Pre-infusion, majority had low ECOG scores (0-1, 81%), including 71% categorized as frail by FP. At pre-infusion FP, 35% of pts were fit (score 0), 44% were prefrail (score 1-2) and 21% were frail (score 3-5). Frail pts were more likely to be admitted for >7d for their CART infusion (OR 7.0, 95% CI 1.02-47.97, p=0.04). Frailty was not associated with risk of CRS, ICANS or 30-day hospital readmission. 13 pts had died by the time of analysis; all but 2 deaths were related to progressive disease. 2 non-disease related deaths were 1 death from COVID and 1 ICANS-related death from teclistamab after relapse 1 year and 2 years after infusion, respectively. At Day 21 post-infusion, 21% were fit, 57% were prefrail, and 21% were frail. At 1mo post-infusion, 25% were fit, 63% were prefrail, and 13% were frail. Being frail by FP at pre-infusion (p<0.001), Day 21 (p=0.03) or 1 month (p=0.009) post-infusion was associated with inferior OS from that time point. Median PFS in pre-infusion fit, prefrail, and frail pts were 23.4mo (95% CI 17.1-NR), 18.4mo (95% CI 6.8-13.8) and 4.0mo (95% CI 2.5-8.4), respectively. 2-year OS estimates were 100%, 93% and 14%, in fit, prefrail and frail pts respectively. 14 of 36 pts maintained or improved their FP from pre-infusion to 1mo; all but 3 received physical therapy (PT) while in hospital with 5 pts continuing PT outpatient. Notably, pts who maintained or improved their FP from pre-infusion to 1mo post-infusion had significantly better OS (p=0.05) than pts who had declines in their scores. Along with pre-infusion, day 21 and 1mo post-infusion FP scores, LDH (Mean 182 U/L) at the time of CART infusion was significantly associated with OS in the univariate Cox proportional hazards model (HR 5.22, 95% CI 1.43-19.18, p=0.013). Several factors including disease type, number of prior lines of therapy, use of bridging, stage at CART, IPI/RISS at diagnosis, HCT-CI, ECOG, presence of extra-nodal disease, CRS, ICANS, gender, age by decade, and BMI did not correlate with outcome. In pts ≥ 60 with R/R lymphoma/MM undergoing CART, 21% were frail by FP prior to CART. Frailty by FP pre-infusion, day 21 and 1mo post-infusion was associated with inferior OS as opposed to ECOG, HCT-CI, age or several disease related risk factors. FP may improve risk stratification in older adults undergoing CART. Pts with improvement in FP within 1mo post-infusion also had better outcomes. While better disease control could contribute to improved FP scores, most pts received PT to reverse frailty. Our future work aims to implement an exercise regimen to improve outcomes and to determine whether frailty is associated with adverse disease biology. Future work to uncover biologic mechanisms of frailty and adverse disease biology may identify novel targets for intervention to improve outcomes for frail pts.
Blood · 2025-11-03
articleAbstract 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.
Blood · 2025-11-03
articleOpen accessAbstract Introduction: Second-line (2L) anti-CD19 CAR T-cell therapy (CART) with axicabtagene ciloleucel (axi) or lisocabtagene maraleucel (liso) is standard-of-care for patients (pts) with large B-cell lymphomas (LBCLs) who relapse within 12 months after frontline treatment. However, determinants of response and toxicity in 2L real-world settings remain poorly defined. Methods: We retrospectively analyzed 64 consecutive LBCLs pts treated at our institution with 2L axi (n=35) or liso (n=29) between 05/2022 and 12/2024. Multiparameter spectral immunophenotyping (Citek) was performed on peripheral blood collected at apheresis and day 7 post-CART. The primary objectives were to compare the two products in a real-world setting and to identify predictors of efficacy and toxicity. Results: Median age at time of CART was 62 years (21-80yrs); 59% had primary refractory LBCL, 17% had an HGBL, 66% had III/IV-stage and 38% had elevated LDH at infusion. Median vein-to-vein time was 42 days (median axi=36 vs liso=43; p=0.03). Bendamustine was used for lymphodepletion in 89% (axi=83% vs liso=96%, p=0.1). Overall and complete response rates (ORR and CR) at day 90 were 66% and 55%.At a median follow-up of 17 months (4-34mo), 12-month PFS and OS rates were 47% and 78%. Efficacy was comparable between axi and liso (12-month PFS: 51% vs 48%, p=0.8; best CR: 51% vs 58%, p=0.6), despite older age (mean 56 vs 66yrs, p<0.01) and higher IPI (≥3 in 28% vs 72%, p<0.01) in the liso cohort.Cytokine release syndrome (CRS) of any grade occurred in 52% of pts (G≥3 = 3%) and neurotoxicity (ICANS) in 12% (G≥3 = 3%). No non-relapse mortality or secondary malignancies occurred. Axi was associated with higher toxicity, with increased rates of CRS (any grade: 80% vs 17%, p<0.01) and a trend towards higher ICANS (any grade: 20% vs 3%, p=0.06). Due to few severe CRS/ICANS events, comparisons between axi and liso were not performed.Disease reassessment after bridging therapy was available for 92% of pts and 34% were infused in progression. Pts infused with progressive disease had worse outcomes as compared to those with disease control: CR as best response in 15% vs 73% (OR=0.06 95%CI=0.01-0.3, p<0.01), 12-month OS 48% vs 91% (p<0.01), and PFS 21% vs 59% (p<0.01). Bulky disease, extranodal involvement, and elevated LDH at infusion were negative predictors of durable response (defined as PFS≥12 months); interestingly these features were not prognostic when analyzed at the relapse after the frontline therapy.Given the prognostic value of clinical variables at infusion but not at relapse, we explored flow cytometry to identify early predictors of treatment response. Higher CD3⁺ and CD4⁺ T-cell counts at apheresis predicted PFS and CR to CART. Optimal cutoffs (401 CD3⁺/µL, 201 CD4⁺/µL) stratified pts with significantly prolonged 12-month PFS rates (59% vs 29% for CD4⁺; p<0.01). High Naive CD4⁺ T-cell at apheresis strongly correlated with durable responses and prolonged PFS (12-month PFS rates: 12% vs 87%, p<0.01).At day 7, responders showed a trend toward greater CART expansion (CAR⁺/CD3⁺: 17% vs 6%, p=0.1) and higher frequencies of naive CD8⁺CART. In contrast, pts infused with progressive disease had numerically lower CART expansion and a more differentiated effector memory phenotype (CAR+/CD3+: 5% vs 14%, p=0.1 and CD45RA-/CCR7-: 54% vs 38%, p=0.3). CAR⁻ bystander T-cells showed a more naive CD4⁺ and less effector CD8⁺ profile indicating functional divergence from CART.In multivariate analysis including CD4⁺ count at apheresis, disease progression at infusion, and primary refractory status, higher CD4⁺ count remained independently associated with higher odds of CR (OR=4.31, 95%CI=1.15-18.8, p=0.03). Progressive disease at infusion (OR=0.06, 95%CI=0.01-0.3, p<0.01) and primary refractory disease(OR=0.2, 95%CI=0.05-0.8, p=0.03) were associated with lower odds of CR. Conclusions: This is the first real-world study to define clinical and immune correlates of efficacy in 2L CART therapy for LBCL. Both axi and liso are safe and effective. Naïve CD4⁺ T-cell abundance at apheresis predicts long-term outcomes and may serve as a biomarker of T-cell fitness and CART potency. Progressive disease at the time of infusion is associated with inferior response rates and survival outcomes, which may be due to less favorable expansion kinetics and T-cell phenotypes. These findings support immune profiling at apheresis and rational bridging to improve outcomes in early-line CART therapy.
Blood · 2025-11-03
articleOpen accessAbstract Chimeric Antigen Receptor (CAR-T) therapy has transformed treatment for non-Hodgkin lymphoma (NHL) and is now standard as early as second line in eligible patients. Its use in older adults (historically considered high-risk for toxicity), has increased the interest in identifying predictors of outcomes given the wide variability of fitness in this population. Body composition parameters are increasingly used in oncology as an objective measure of physiological reserve and frailty. It can be assessed using routine CT scans to evaluate both the quantity and quality of muscle and fat. Skeletal muscle index (SMI), calculated at the L3 level by dividing muscle area by height squared, is used to assess sarcopenia. Skeletal muscle density (SMD) reflects fat infiltration within muscle, with lower Hounsfield Unit (HU) values indicating myosteatosis. Adipose tissue is categorized into subcutaneous (SAT) and visceral (VAT) compartments ( in cm2), and their densities (SATD and VATD) offer additional clinical insight. Higher adipose density (closer to 0 HU) reflects reduced lipid content and is linked to inflammation and fibrosis, while lower density suggests healthier fat. In patients with NHL undergoing autologous stem cell transplant, lower VATD has been associated with better survival (Aleixo et al., 2019). In this single-center retrospective cohort of older adults with NHL treated with CAR T-cell therapy, we hypothesize that body composition parameters may serve as markers of frailty associated with worse survival and clinical outcomes. Methods We conducted a single-center retrospective cohort study of consecutive patients aged ≥65 years who received CAR T-cell therapy for NHL between 2019 and 2025. CT scans within 45 days before and 90 days after infusion were analyzed to estimate body composition parameters, including SMI, SAT, VAT, and their densities. Baseline characteristics were summarized descriptively. Pre- and post-infusion body composition metrics were then compared between age groups (65–75 vs. >75 years) using Wilcoxon rank-sum tests for cross-sectional differences. Overall Survival (OS) was defined from infusion to death or last follow-up and analyzed using Kaplan-Meier curves and Cox models. Logistic regression was used to evaluate associations between clinical and body composition variables with infections within 180 days. Univariate analyses were followed by a multivariable model. Results A total of 153 patients were included; 135 had baseline CT scans, 124 had 90-day scans, and 106 had both available for delta calculations. The median age was 71 years (IQR 68–75). Most patients (84%) had diffuse large B-cell lymphoma, including 9% with double-hit disease; 7% had follicular lymphoma, 9% had mantle cell lymphoma, and 1% had chronic lymphocytic leukemia. Overall, 62% had received more than two prior lines of therapy, and CHOP-based regimens were the most common first-line treatment (65%). Tisagenlecleucel was the most frequently used CAR T-cell product (62%). Patients over 75 years had significantly lower skeletal muscle mass both at baseline (SMI 36.6 vs. 40.33, p=0.02) and at 90 days post-infusion (SMI 35.8 vs. 40.9, p=0.029) compared to patients aged 65–75. However, the change in SMI over time did not differ significantly between age groups (p=0.391). No significant differences were observed between age groups in other body composition parameters. After adjusting for age, CAR T-cell product, ECOG performance status, BMI, and number of prior therapies, higher post-therapy VATD (HR 1.04, 95% CI 1.02–1.05, p < 0.001) and SATD (HR 1.03, 95% CI 1.01–1.04, p = 0.001) remained independently associated with shorter overall survival. Furthermore, each unit increase in VATD or SATD from baseline to 90 days post-CAR-T further portended worse outcome (VATD: HR 1.05, 95% CI 1.02–1.1, p = 0.001; SATD: HR 1.04, 95% CI 1.02–1.07, p = 0.001). Similarly, higher post-therapy SATD (Odds Ratio (OR) 1.04, 95% CI 1.01–1.07, p = 0.003) and increases in SATD at 90 days post-CAR-T (OR 1.04, 95% CI 1.01–1.09, p = 0.01) were associated with increased risk of infection within 180 days. Conclusion Our findings suggest that higher adipose tissue density is associated with worse survival and increased infection rates in older adults with NHL treated with CAR T-cell therapy. These results support further investigation of adiposity markers as objective, imaging-based indicators of frailty.
Frequent coauthors
- 540 shared
Stephen J. Schuster
University of Pennsylvania
- 501 shared
Sunita D. Nasta
University of Pennsylvania
- 405 shared
Daniel J. Landsburg
- 352 shared
Elise A. Chong
Hospital of the University of Pennsylvania
- 227 shared
Stefan K. Barta
- 153 shared
James N. Gerson
University of Pennsylvania
- 147 shared
Anthony R. Mato
- 133 shared
Marco Ruella
University of Pennsylvania
Labs
Jakub Svoboda LaboratoryPI
Awards & honors
- Member, Abramson Cancer Center, Data Safety Monitoring Commi…
- Conference Co-Chair, Updates in Care of the Hematologic Mali…
- Conference Co-Chair, Focus on Leukemia, Lymphoma, Myeloma, a…
- Long-term safety of lentiviral or gammaretroviral gene-modif…
- Brentuximab vedotin plus AVD for Hodgkin lymphoma: incidence…
- Resume-aware match score
- Save to shortlist
- AI-drafted outreach
See your match with Jakub Svoboda
PhdFit ranks faculty by your research interests, methods, and publications — grounded in their actual work, not templates.
- Free to start
- No credit card
- 30-second signup