Association of PET4 response with outcomes of BV-CHP vs CHOP in the ECHELON-2 trial in CD30+ peripheral T-cell lymphoma Swaminathan Iyer, Neha Mehta-Shah, Ranjana Advani, Nancy L. Bartlett, Jacob H. Christensen, et al. Blood Advances, 2025 In the phase 3 ECHELON-2 trial, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (BV-CHP) significantly improved progression-free survival (PFS) and overall survival (OS) compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with CD30+ peripheral T-cell lymphoma, benefits that were maintained at 5 years. Interim positron emission tomography (PET) scan can be used to assess prognosis and risk-stratify patients. The prognostic value of interim PET was assessed in this post hoc exploratory analysis from ECHELON-2, evaluating interim 18F-fluorodeoxyglucose PET scans after cycle 4 (PET4) and end-of-treatment–based response, and correlated with PFS per investigator and OS. PET4 response was determined by Deauville score (scores of 1-3 were considered negative [PET4-negative] and 4-5 positive [PET4-positive]) by independent review. Overall, 452 patients were randomized 1:1 to the BV-CHP (n = 226) and CHOP (n = 226) arms. Of these, 32 in the BV-CHP arm and 41 in the CHOP arm were not evaluable for PET4. In both arms, PET4-negative status was associated with improved PFS (BV-CHP: HR, 0.36; 95% CI, 0.19-0.66; CHOP: HR, 0.26; 95% CI, 0.17-0.41) and OS (BV-CHP: HR, 0.38; 95% CI, 0.18-0.78; CHOP: HR, 0.24; 95% CI, 0.14-0.41) compared with PET4-positive status. Among patients with systemic anaplastic large cell lymphoma, PET4-negative patients had improved PFS (BV-CHP: HR, 0.28; 95% CI, 0.14-0.60; CHOP: HR, 0.31; 95% CI, 0.17-0.56) and OS (BV-CHP: HR, 0.38; 95% CI, 0.16-0.94; CHOP: HR, 0.25; 95% CI, 0.12-0.55) compared with PET4-positive patients. In this exploratory analysis, PET4-negative status by Deauville score was associated with improved long-term PFS and OS in both the BV-CHP and CHOP arms. This trial was registered at www.ClinicalTrials.gov as #NCT01777152.
Efficacy and Safety of Glofitamab Plus Polatuzumab Vedotin in Relapsed/Refractory Large B-Cell Lymphoma Including High-Grade B-Cell Lymphoma: Results From a Phase Ib/II Trial Martin Hutchings, Anna Sureda, Francesc Bosch, Thomas Stauffer Larsen, Paolo Corradini, et al. Journal of Clinical Oncology, 2025 PURPOSE An unmet need remains for more effective therapies for relapsed/refractory (R/R) large B-cell lymphoma (LBCL), especially high-grade B-cell lymphoma (HGBCL). We present the primary analysis of a phase Ib/II study (ClinicalTrials.gov identifier: NCT03533283 ) investigating efficacy and safety of glofitamab plus polatuzumab vedotin (Glofit-Pola) in patients with R/R LBCL, including HGBCL and those who received previous chimeric antigen receptor (CAR) T-cell therapy. METHODS Patients received 1,000 mg obinutuzumab on Cycle (C)1 Day (D)1 (once daily). Polatuzumab vedotin (1.8 mg/kg) was given on C1D2 and D1 of C2–6 (21-day cycles; once daily). Glofitamab was given as step-up doses in C1 (D8, 2.5 mg; D15, 10 mg) followed by 30 mg on D1 of C2–12 (21-day cycles; once daily). Polatuzumab vedotin was given for six fixed-duration cycles, and glofitamab for 12. RESULTS As of September 2, 2024, 129 patients with LBCL (HGBCL; n = 44, 34.1%), received ≥1 dose of study treatment. The median age was 67 years (range, 23-84), and 63.6% were male. Patients had received a median of 2 (range, 1-7) previous lines of treatment (previous CAR T-cell therapy, n = 28, 21.7%). The independent review committee–assessed overall response rate was 78.3% (complete response rate, 59.7%). The median progression-free survival and overall survival (OS) were 12.3 and 33.8 months, respectively (median OS follow-up time, 32.7 months). The most common adverse event (AE) was cytokine release syndrome (43.4%; grade 1-2: 41.9%; one grade 5 event). Grade 3-4 AEs occurred in 58.9% of patients; 9.3% had grade 5 AEs, and 14.7% discontinued treatment because of AEs. CONCLUSION Glofit-Pola demonstrated high efficacy and durable responses, with manageable safety, in heavily pretreated patients with R/R LBCL, including patients with HGBCL and previous CAR T-cell therapy failure.
Enhancing the diagnostic accuracy of core needle biopsy in patients with lymphoproliferative disorders by an optimized protocol Silvia Ferrari, Alessandra Weber, Paolo Marra, Paola Tebaldi, Chiara Pavoni, et al. Radiologia Medica, 2025 Purpose Surgical excision biopsy of lymph nodes stands as the gold standard for histological characterization of lymphoproliferative disorders (LD). However, contemporary clinical practice increasingly leans toward core needle biopsy (CNB). This study seeks to explore the factors influencing the diagnostic yield of CNB in LD. Material and Methods This unicentric retrospective study presents data from patients referred for suspicion of new or relapsing LD. All patients underwent image-guided CNB of the target lesion based on PET/CT findings. The primary endpoint was the diagnostic outcome, comparing the ability to achieve a definitive diagnosis according to international guidelines with CNB versus the necessity for subsequent excisional biopsy. Results We enrolled 478 consecutive patients undergoing CNB, categorized into two cohorts. Cohort A comprised patients who underwent CNB using 18-20G full-core Menghini needles, with a median macroscopic fragment dimension of 1 cm. Cohort B included patients who underwent CNB with 16-18G semiautomatic guillotine needles, with a median macroscopic fragment dimension of 1.5 cm. In cohort A, the rates of diagnostic and non-diagnostic (or non-sufficiently detailed) CNBs were 95 (73%) versus 35 (27%), respectively. In cohort B, these rates were 299 (86%) versus 49 (14%). Conclusion The type and size of the needle used for CNB, as well as the histologic variant of LD, emerged as factors influencing diagnostic yield and accuracy. Given the swiftness of CNB compared to surgical excision, optimizing this technique could streamline the diagnostic and therapeutic workflow for patients with suspected LD.
Preclinical development of anti-CD21 chimeric antigen receptor T cells to treat T cell acute lymphoblastic leukemia Nicola Maciocia, Malika Hoekx, Ciaran Acuna, Brandon Wade, Amy Burley, et al. Science Translational Medicine, 2025 Patients with relapsed/refractory (r/r) T cell acute lymphoblastic leukemia (T-ALL) have a dismal prognosis, highlighting the urgent need for effective therapies. Chimeric antigen receptor (CAR)–T cell approaches targeting pan–T cell antigens may be limited by T cell aplasia and fratricide, necessitating “rescue” allogeneic hematopoietic stem cell transplantation. In this study, we identify CD21, a pan–B cell marker, as a promising target for T-ALL immunotherapy. CD21 is expressed in 50% of T-ALL cases at diagnosis but in fewer than 10% of mature T cells. We observed that CAR-T cells targeting membrane-distal CD21 epitopes were ineffective, likely because of the bulky, glycosylated nature of the antigen. However, when we engineered CAR-T cells to target membrane-proximal CD21 epitopes using an antigen-binding fragment (Fab)–CAR design, we demonstrated robust activity against T-ALL cell lines, primary tumors, and patient-derived xenografts in both in vitro and in vivo models. The enhanced efficacy of this Fab-CAR design was driven by its high stability and reduced surface expression, addressing limitations of traditional CAR constructs. In addition, pharmacological inhibition of the phosphatidylinositol 3-kinase axis up-regulated CD21 expression in T-ALL, further enhancing the potency of anti-CD21 CAR-T cells in vitro and in a patient-derived xenograft in vivo model. This study establishes CD21 as a viable CAR-T target and highlights advances in CAR design for bulky antigens, as well as the potential for pharmacological strategies to augment target expression. Anti-CD21 CAR-T cells represent a promising therapeutic option for improving outcomes for patients with T-ALL.