CD19 CAR T‐Cell Therapy in Primary Cutaneous Diffuse Large B‐Cell Lymphoma, Leg Type

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a rare, aggressive cutaneous B-cell lymphoma, typically affecting older adults with rapidly enlarging tumors on the lower extremities and frequent extracutaneous dissemination 1. PCDLBCL-LT is genetically distinct from other primary cutaneous B-cell lymphomas, most notably from primary cutaneous follicle center lymphoma, instead showing an activated B-cell-like phenotype with recurrent mutations in CD79B, CARD11, and MYD88 driving NF-κβ activation 2-4. The enrichment for MYD88 and CD79B aberrations clusters PCDLBCL-LT in the so-called C5 genetic signature, highlighting overlapping features with B-cell lymphomas of immune-privileged sites, including testicular and central nervous system (CNS) lymphoma, all of which display extranodal tropism 5. While PCDLBCL-LT shares this genetic profile, the C5 cluster represents a shared molecular program rather than a single clinicopathologic entity; in contrast to other non-GCB C5-cluster DLBCLs, PCDLBCL-LT shows a marked tropism for the skin, suggesting that this entity is a distinct clinicopathologic disease rather than merely a cutaneous presentation of other systemic C5-DLBCLs. PCDLBCL-LT may display inherent chemoresistance and high relapsability at cutaneous and systemic sites, including the CNS 6-8. As such, salvage therapy is often needed. While CD19-directed chimeric antigen receptor (CAR) T-cell therapy has transformed outcomes in relapsed/refractory large B-cell lymphomas 9-14, the vast majority of patients enrolled in pivotal trials and treated to date have had DLBCL, not otherwise specified—therefore, the representation and outcomes of PCDLBCL-LT within this paradigm are undefined. For example, in the ZUMA-7 trial of axicabtagene ciloleucel (axi-cel) as second-line therapy in DLBCL, only one patient of 359 had PCDLBCL-LT 13. Similarly, in the TRANSFORM trial of lisocabtagene maraleucel (liso-cel) as second-line therapy in DLBCL, PCDLBCL-LT was excluded from enrollment 15. Acknowledging this knowledge gap and the frequent need for salvage therapies in PCDLBCL-LT, we aimed to determine outcomes with commercial CD19 CAR T-cells in this distinct entity. This international, multicenter retrospective study included consecutive PCDLBCL-LT patients from Memorial Kettering Cancer Center (New York, US), Hackensack Meridian Health (New Jersey, US), and Rambam Health Care Campus (Haifa, Israel), who received commercial CD19 CAR T-cells (axi-cel, liso-cel, and tisagenlecleucel tisa-cel) between 2018 and 2025. The Institutional Review Boards of the participating institutions approved the study in accordance with the Declaration of Helsinki. Data were collected via chart review. Response assessment was performed according to Lugano criteria as documented in the medical record, with best response defined as the best response achieved within 365 days of infusion. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per the American Society for Transplantation and Cellular Therapy criteria. Progression-free survival (PFS) was defined from CAR T-cell infusion to the earliest documented relapse/progression or death from any cause. Initiation of a subsequent therapy before relapse/progression was treated as a censored event. Overall survival (OS) was calculated from CAR T-cell infusion to the date of last follow-up. Deaths without prior documented relapse/progression were considered competing events. We identified five patients with relapsed/refractory PCDLBCL-LT treated with CAR T-cells (Table 1). The median age at infusion was 70 years (range, 60–76) and the median number of prior lines of therapy was 2 (range, 1–4). All patients had received prior anthracycline-containing combination chemotherapy (R-CHOP). Two patients received liso-cel, two received axi-cel, and one received tisa-cel. All patients underwent bridging therapy and underwent lymphodepletion with cyclophosphamide and fludarabine. At the time of infusion, disease distribution was skin only in two patients, skin plus extracutaneous sites in two patients, and CNS only in one patient. Best responses to CAR T-cell therapy were one complete response (CR), two partial responses (PR), one stable disease (SD), and one progressive disease (PD), resulting in an overall response rate (ORR) of 60% (Figure 1). Among the three responders, the median duration of response was at 4.2 months (range: 1.4–6.9). The patient achieving CR remained relapse-free until death at 6.9 months from non-disease, non-therapy-related causes (end-stage renal disease on dialysis pre-existing to CAR T-cell infusion). All other patients progressed—the two patients with PRs progressed at 4.2 and 1.4 months, respectively, and the patient with SD progressed at 3.4 months. The initial sites of progression were skin in three patients (one with skin only and two with skin, nodal, and/or visceral involvement) and isolated CNS in one patient (the patient with CNS disease at infusion). Among progressions with tissue available (three patients), none were definitively CD19-negative (see representative patient, Figure 2). For all patients, the median PFS and OS was 3.4 (range: 0.7–6.9) and 6.9 (range: 0.9–11.4) months, respectively. Post-progression therapies were heterogeneous and are shown in Table 1. At data cutoff, only one patient remained alive and is receiving ongoing therapy. Any-grade CRS occurred in three patients (with no grade ≥ 3 CRS), and ICANS occurred in two patients, both grade ≥ 3. CD19 CAR T-cell therapy has fundamentally changed the landscape of treatment for DLBCL, though for rare subtypes, such as PCDLBCL-LT, the exact efficacy is not established. PCDLBCL-LT is a unique DLBCL subtype given its genetic makeup and presenting anatomical site, and these two features, which dictate immune and microenvironmental features and T-cell access, likely play important roles in drug efficacy. In this series of PCDLBCL-LT treated with commercial CD19 CAR T-cell products, responses were observed (ORR 60%), but durability was limited, with most patients relapsing early, frequently at cutaneous sites. Median OS (6.9 months) was suboptimal and inferior to broad real-world DLBCL benchmarks, highlighting the challenging nature of PCLBCL-LT. Beyond histology, we and others have recently shown that the anatomic site of disease shapes CAR T-cell performance in DLBCL, with heterogeneous response and relapse hazards by extranodal compartment 16, 17. The skin is a biologically distinct niche, and while early cellular therapy experiences in cutaneous T-cell lymphoma demonstrate that engineered T cells can traffic to and act within skin 18, 19, this unique microenvironment coupled with the genetic program of PCDLBCL-LT likely affects overall efficacy. Indeed, in our cohort, the pattern of failure was dominated by the cutaneous compartment—three out of the four initial progressions involved the skin. Moreover, despite small numbers, there was no evidence of CD19 antigen loss among assessable tumors, which suggests CAR T-cell failure mechanisms other than target escape and points more toward site-conditioned resistance. Several interlocking features of the cutaneous niche plausibly blunt CAR T-cell activity, including constrained trafficking and retention through a dense extracellular matrix and specialized dermal vasculature, sustained inhibitory signaling within a PD-L1/PD-L2–rich 20, macrophage-dominant milieu, and survival circuitry anchored in MYD88/CD79B 21 and downstream NF-κB signaling that reinforces both tumor fitness and microenvironmental crosstalk 22, 23. Taken together, this landscape favors functional exhaustion over outright antigen loss, a pattern parallel with the biology of other immune-privileged territories and with lesion-level heterogeneity reported in broader DLBCL cohorts 16. Still, the unique dermal immune niche of PCDLBCL-LT is likely a key distinction from other non-GCB C5-cluster DLBCLs lacking predominant cutaneous involvement, with direct implications for CAR T-cell trafficking, persistence, and efficacy. Clinically, this series underscores anatomical sites of disease, in particular the skin, in considering the potential efficacy of CAR T-cell therapy. Other agents have salvage activity in PCDLBCL-LT, namely checkpoint inhibitors, BTK inhibitors, and immunomodulatory agents, such as lenalidomide 24-26. How these agents position relative to CAR T-cell therapy for PCDLBCL-LT is unclear, though one can imagine rational combinations, use as consolidation, or use for low-level relapse or progression. Checkpoint blockade could be deployed selectively, particularly in PD-L1–positive relapse or smoldering cutaneous persistence to reinvigorate exhausted CAR T cells 18, 19, 27. In parallel, agents that temper chronic active B-cell receptor and NF-κB signaling—ibrutinib and lenalidomide—could offer direct antitumor activity and immunomodulation that may improve T-cell function. Their role as carefully dosed bridging therapy to optimize cytoreduction and fitness or as post-CAR T-cell consolidation or maintenance deserves prospective evaluation, though we acknowledge the frank rarity of this disease 24-26. In summary, this report suggests that commercial CD19 CAR T-cell therapy can induce responses in PCDLBCL-LT, but early, often cutaneous, relapse and progression is common. Despite the limitation of a small sample size, our findings underscore the challenges in treating PCDLBCL-LT and emphasize the skin as a unique disease site. While prospective efforts are unlikely given the rarity of this entity, rational CAR T-cell combinations that incorporate skin-directed bridging or consolidative strategies, such as radiotherapy, or other active agents in PCDLBCL-LT, such as lenalidomide or BTK inhibitors, may represent therapeutic options in this biologically distinct lymphoma. The reported research was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) Memorial Sloan Kettering Cancer Center Support Grant (P30 CA008748). S.E.-S. received support from the Alfonso Martín Escudero Foundation through the award of the FUNDAME fellowship. R.S. (Stuver) is supported by the Lymphoma Research Foundation. This work was supported by the National Institutes of Health (P30 CA008748). The Institutional Review Boards of the participating institutions approved the study in accordance with the Declaration of Helsinki. S.E.-S., O.B.-K., P.B.D., S.G., M.G.-L., A.G., C.L., E.L., A.M., M.P., A.S., and C.A.V. have no disclosures. R.S. (Shouval) reports Honoraria from Sanofi, MSD, and Incyte. S.E. reports institutional research funding from MSD and Honoraria from Sanofi. S.M.H. has research support from ADC Therapeutics, Affimed, Celgene, Corvus, Crispr Therapeutics, Daiichi Sankyo, Kyowa Hakko Kirin, Takeda, Seattle Genetics, Treeline, Trillium Therapeutics, and SecuraBio; consulting from Arvinas, BlueSphere Bio, Corvus, Daiichi Sankyo, DrenBio, J consulting or advisory roles with Affyimmune Therapeutics, Allogene Therapeutics, Amgen, Artiva Biotherapeutics, Autolus, Be Biopharma, Beigene, BMS, Bright Pharmaceutical Services Inc., Caribou Biosciences, Curocell, Galapagos, GreenCross Biopharma, In8Bio, Kite, Medpace, Minerva Biotechnologies, Pfizer, Servier, Sobi, Takeda. He reports research funding from Autolus, Genentech, Fate Therapeutics, InCyte, Servier. M.-A.P. reports honoraria from Allogene, Celgene, Bristol-Myers Squibb, Exevir, ImmPACT Bio, Incyte, Kite/Gilead, Merck, Miltenyi Biotec, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Pierre Fabre, Sanofi, Syncopation, Takeda, VectivBio AG, and Vor Biopharma; he serves on DSMBs for Cidara Therapeutics and Sellas Life Sciences; he has ownership interests in Omeros and OrcaBio; he has received institutional research support for clinical trials from Allogene, Genmab, Incyte, Kite/Gilead, Miltenyi Biotec, Novartis, and Tr1x. K.R. reports research funding, consultancy, honoraria and travel support from Kite/Gilead; honoraria from Novartis; consultancy, honoraria from BMS/Celgene; travel support from Pierre-Fabre; consultancy from CSL Behring. J.R. received honoraria from Astra Zeneca for participation in advisory boards, alongside research support from Astra Zeneca, Bristol Myers Squibb, Genentech, and AbbVie. G.S. (Salles) received in the last 12 months financial compensations for participating in advisory boards at AbbVie, BeiGene, BMS, Genentech/Roche, Genmab, Janssen, Kite/Gilead, Merck, Novartis, Pfizer, Incyte, Ipsen.; received support from AbbVie, Genentech, Genmab Janssen, Ipsen, and Nurix, which was managed by his institution. C.S. reports serving as a paid consultant/adviser for Kite/a Gilead company, Celgene/BMS, Gamida Cell, Karyopharm Therapeutics, Ono Pharmaceuticals, MorphoSys, CSL Behring, Syncopation Life Sciences, CRISPR Therapeutics, and GlaxoSmithKline; and receiving research funding from Juno Therapeutics, Celgene/BMS, BMS, Precision Biosciences, Actinium Pharmaceuticals, Sanofi-Genzyme, Cargo Therapeutics, Affimed, and Nkarta. M.S. served as a paid consultant for McKinsey received research funding from Angiocrine Bioscience Inc., Omeros Corporation, Amgen Inc., Bristol Myers Squibb, and Sanofi; served on ad hoc advisory boards for Kite—A Gilead Company, and Miltenyi Biotec; and received honoraria from i3Health, Medscape, CancerNetwork, Intellisphere LLC, Curio Science LLC, and IDEOlogy. G.S. (Shah) has consulting or advisory roles at Arcell; research funding from Janssen (Inst), Amgen (Inst), BeyondSpring Pharmaceuticals (Inst), Bristol Myers Squibb/Celgene (Inst), GPCR Therapeutics (Inst), Recordati (Inst); M.L.P. reports the following: Synthekine: Consultancy; Novartis: Consultancy; Bristo Meyer Squibb: Consultancy; Cellectar: Consultancy. A.I. reports the following: Consulting/honoraria: Genmab, Seagen, Gilead/KITE, AstraZeneca; R.S. has research support (all paid to institution) from Pfizer and Step Pharma. The data that support the findings of this study are available from the corresponding author upon reasonable request.