Secondary Central Nervous System Involvement Research Articles

Feasibility of Circulating Tumor DNA Detection in the Cerebrospinal Fluid of Patients With Central Nervous System Involvement in Large B-Cell Lymphoma.

We explored the utility of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) sequencing as a noninvasive diagnostic tool for detecting central nervous system (CNS) involvement in patients with diffuse large B-cell lymphoma (DLBCL). Secondary CNS involvement in DLBCL, although rare (~5% of cases), presents diagnostic and prognostic challenges during systemic disease progression or relapse. Effective treatment is impeded by the blood-brain barrier. This was a prospective cohort study (Samsung Lymphoma Cohort Study III) involving 17 patients with confirmed CNS involvement. High-throughput sequencing was conducted using targeted gene panels designed to detect low-frequency variants and copy number alterations pertinent to lymphomas in ctDNA extracted from archived CSF samples. Despite challenges such as low DNA concentrations affecting library construction, the overall variant detection rate was 76%. Detected variants included those in genes commonly implicated in CNS lymphoma, such as MYD88. The study highlights the potential of CSF ctDNA sequencing to identify CNS involvement in DLBCL, providing a promising alternative to more invasive diagnostic methods such as brain biopsy, which are not always feasible. Further validation is necessary to establish the clinical utility of this method, which could significantly enhance the management and outcomes of DLBCL patients with suspected CNS involvement.

Clinical characteristics and outcome of early-stage diffuse large B cell lymphoma of female genital track: A retrospective study of the Hellenic cooperative lymphoma group.

Involvement of female genital track (FGT) by diffuse large B cell lymphoma (DLBCL) represents an extremely rare diagnosis. Especially data regarding early-stage disease (i.e., IE, IIE) is very limited. Importantly, previous studies showed controversial results about the risk of central nervous system (CNS) relapse in this entity. Herein, we describe one of the largest reported real-world series of patients with early-stage FGT DLBCL aiming to investigate the clinicopathological characteristics, response to therapy and survival outcomes in the era of immunochemotherapy. We analyzed 21 consecutive patients with biopsy proven DLBCL from uterus or ovary classified as stage IE or IIE out of 1905 newly diagnosed DLBCL patients (1.1%). Uterine and ovarian localization was observed in 14 and seven patients, respectively. Median age was 66years (range 33-96); 9/21 (43%) were <55years. Regarding Cell of Origin DLBCL subtype, Germinal Center B-cell subtype was found in seven patients, non-GCB in 10 and non-classified in 4 patients. Median follow-up was 57months and 5-year overall survival, lymphoma specific survival and Freedom from Progression were 78%, 89% and 90%, respectively. There was no correlation of patients' characteristics with survival parameters. Interestingly, none of the patients experienced CNS relapse. Our results indicate that localized FGT DLBCL exhibits a good prognosis and may not increase the risk for secondary CNS involvement.

CAR T-cell therapy in mantle cell lymphoma with secondary CNS involvement: a multicenter experience

Secondary central nervous system (CNS) involvement in Mantle cell lymphoma has poor outcomes, with limited data for efficacy of CAR-T therapy. This study reports encouraging response with reasonable safety profile, but risk of CNS relapse remains high in such patients.

Treatment of secondary CNS lymphoma using CD19-targeted chimeric antigen receptor (CAR) T cells

BackgroundAggressive B cell lymphoma with secondary central nervous system (CNS) involvement (SCNSL) carries a dismal prognosis. Chimeric antigen receptor (CAR) T cells (CAR-T) targeting CD19 have revolutionized the treatment for B cell lymphomas; however, only single cases with CNS manifestations successfully treated with CD19 CAR-T have been reported.MethodsWe prospectively enrolled 4 patients with SCNSL into our study to assess clinical responses and monitor T cell immunity.ResultsTwo of four SNCSL patients responded to the CD19-targeted CAR-T. Only one patient showed a substantial expansion of peripheral (PB) CAR-T cells with an almost 100-fold increase within the first week after CAR-T. The same patient also showed marked neurotoxicity and progression of the SNCSL despite continuous surface expression of CD19 on the lymphoma cells and an accumulation of CD4+ central memory-type CAR-T cells in the CNS. Our studies indicate that the local production of chemokine IP-10, possibly through its receptor CXCR3 expressed on our patient’s CAR-T, could potentially have mediated the local accumulation of functionally suboptimal anti-tumor T cells.ConclusionsOur results demonstrate expansion and homing of CAR-T cells into the CNS in SNCSL patients. Local production of chemokines such as IP-10 may support CNS infiltration by CAR-T cells but also carry the potential of amplifying local toxicity. Future studies investigating numbers, phenotype, and function of CAR-T in the different body compartments of SNSCL patients receiving CAR-T will help to improve local delivery of “fit” and highly tumor-reactive CAR-T with low off-target reactivity into the CNS.

Outcomes of Large B-Cell Lymphoma (LBCL) Patients with Secondary Central Nervous System Involvement Following Chimeric Antigen Receptor T-Cell Therapy: A CIBMTR Analysis

Outcomes of Large B-Cell Lymphoma (LBCL) Patients with Secondary Central Nervous System Involvement Following Chimeric Antigen Receptor T-Cell Therapy: A CIBMTR Analysis

Secondary central nervous system involvement in patients with diffuse large B-cell lymphoma treated with rituximab combined CHOP therapy – a supplementary analysis of JCOG0601

Secondary central nervous system involvement (sCNSi) in diffuse large B-cell lymphoma (DLBCL) is fatal. However, its features in patients with sCNSi who are categorized as lower risk by international prognostic index (IPI) or CNS-IPI are not yet fully understood. In the present analysis, we evaluated DLBCL patients who developed sCNSi at their first progression and who participated in JCOG0601, most of whom were lower risk by IPI. Of 409 patients, 21 (5.1%) developed sCNSi during a median follow-up of 4.9 years. Five-year cumulative incidence of sCNSi were 5.1%; and 4.0%, 5.3%, and 11.5% at low, intermediate, and high risk of CNS-IPI, respectively. The most common locations of extranodal lesions at the time of registration in patients with sCNSi were the stomach (n = 4), paranasal cavity (n = 3), and bone marrow (n = 2). In univariable analysis, paranasal cavity lesion was a high-risk factor for sCNSi (subdistribution hazard ratio, 4.34 [95% confidence interval 1.28–14.73]). Median overall survival after sCNSi was 1.3 years, with a 2-year overall survival rate of 39.3%. The incidence of sCNSi in DLBCL patients at lower risk of CNS-IPI was low, as previously reported, but paranasal cavity lesion might indicate high risk for organ involvement.Clinical trial registrationJCOG0601 was registered in the UMIN Clinical Trials Registry (UMIN000000929, date of registration; December 04, 2007) and the Japan Registry of Clinical Trials (jRCTs031180139, date of registration; February 20, 2019).

Outcomes for patients with secondary CNS involvement in relapsed/refractory diffuse large B-cell lymphoma and estimation of eligibility for CAR T-cell therapy

Outcomes for patients with secondary CNS involvement in relapsed/refractory diffuse large B-cell lymphoma and estimation of eligibility for CAR T-cell therapy

Phase II, Single-Center, Prospective Study of Intrathecal Thiotepa for the Prophylaxis of Secondary Central Nervous System Involvement in Highly Aggressive B-Cell Lymphoma

Background Central nervous system (CNS) recurrence of systemic diffuse large B cell lymphoma (DLBCL) is a well-recognized and almost uniformly fatal complication that tends to occur within 2 years of initiating treatment. The probability of CNS relapse in DLBCL ranges from 4 to 7% overall but is increased to 20% in certain subgroups. Evidence supporting the use of intravenous methotrexate (MTX) or arabinoside (AraC) in high-risk patients is growing, however, the use of other agents remains to be defined. Thiotepa (TT) is a polyfunctional alkylating agent first developed in the 1950s. Both thiotepa and its metabolite tepa demonstrate good CNS bioavailability, making thiotepa a useful adjunctive chemotherapy for primary and secondary CNS lymphoma, particularly in the context of hematopoietic stem cell transplant (HSCT). Herein, we conduct this prospective trial to evaluate the efficacy and safety of prophylactic intrathecal thiotepa for the prevention of secondary CNS involvement in patients with DLBCL. Methods Patients The primary end point is 2-year cumulative incidence of CNS. The secondary end points are 2-year progression free survival (PFS), 2-year overall survival (OS), and safety. The main inclusion criteria include: adults patients ≥18 years old; histopathological confirmed DLBCL without previous antitumor therapy; high-risk CNS involvement (one of the following): primary breast or testicular lymphoma, involvement of any of the following organs: testis, breast, kidney, adrenal gland, paranasal sinus, epidural space or uterus; CNS International Prognostic Index (CNS-IPI)≥4; dual protein expression (DE) or double/triple hit (DH/TH) lymphoma. The main exclusion criteria include: Burkitt lymphoma, primary CNS lymphoma, or large B cell lymphoma transformed from indolent lymphoma; the presence of parenchymal or meningeal lymphoma; history of whole brain radiotherapy or craniospinal cord irradiation; obstructive hydrocephalus patients requiring neurosurgical intervention. Treatment protocol The systemic chemotherapy regimen is determined by investigator. All patients are need to receive IT thiotepa 10 mg and dexamethasone 5 mg on day 1 of each cycle of chemotherapy for at least 4 cycles. All patients are asked to lie flat for 4 to 6 hours after the lumbar puncture. Follow-up Routine biochemical and cytological analysis of cerebrospinal fluid is performed for each cycle. Imaging examination, such as brain magnetic resonance imaging (MRI) and body computed tomography (CT), is repeated every 2 cycles of chemotherapy, then every 3 months during follow-up. Results From February 2022 to June, 2023, 27 patients (female 14, male 13) received IT thiotepa. The clinical characteristics are shown in Table 1. The median age was 66 years old (range: 46-74). As first-line chemotherapy, 15 (55.6%) patients received rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (RCHOP), 5 (18.5%) patients received RCHOP+BTK inhibitor, 3 (11.1%) patients received BTK inhibitor, lenalidomide with rituximab (ZR2) followed by RCHOP, and 4 (14.8%) patients received RCHOP with intravenous MTX. Thirteen (48.1%) patients had IPI score 4-6 and 17 (63%) patients had DE of c-myc and bcl-2. All patients received fluorescence in situ hybridization (FISH) cytogenetic testing for C-MYC, BCL-2, BCL-6 and TP53. Four (14.8%) patients had TP53 deletion, and 11 (40.7%) patients had sole rearrangement of C-MYC or BCL-2 or BCL-6, but no one were diagnosed with DH/TH lymphoma. All patient have received IT thiotepa for at least once, and 12 (44.4%) patients completed 4-6 cycles of IT, 84 cycles totally. IT thiotepa was a safe measure, for no one experienced post-LP headache, local infection, bleeding, or cerebral herniation. But there were 4 patients had five times of inability to identify direction and slow speech response. They could recover normally the next day without any treatment. Although the follow-up period was short, no patient developed CNS involvement. Conclusion Prophylactic intrathecal thiotepa is an effective and side-effects manageable measure for preventing secondary central nervous system involvement in high-risk DLBCL. Longer follow-up and larger-scale prospective trial is needed to testify this measure.

Screening Cerebrospinal Fluid for Aggressive B-Cell Lymphoma: Significance of Clonal Populations Found with 8-Color Flow Cytometry

Background: Secondary central nervous system (CNS) lymphoma confers a poor prognosis, and prompt identification is critical for guiding management. Over the last decade, we have employed cerebrospinal fluid (CSF) analysis with 8-color flow cytometry (FCM) in screening patients deemed at risk of CNS relapse. However, there is little data to guide interpretation and management of positive results, and concurrent clinical and radiographic features of FCM positive (FCM+) patients, remain areas of uncertainty. Methods: We analyzed newly diagnosed (ND) and relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) and high grade B cell lymphoma (HGBCL) patients who underwent a screening lumbar puncture (LP) from 2011-2020. Clinical, imaging, and CSF findings (differential, cytology, FCM) were collected. Patients with prior CNS involvement or FCM showing CLL/low-grade B-NHL were excluded. “FCM-only” patients were defined as FCM+ but without any other evidence of CNS spread (negative cell count/cytology, MRI, and no symptoms), whereas others were deemed to have overt CNS disease. Results: There were 415 LPs among 361 patients (243 ND, 172 R/R). 21 (5%) patients were FCM+, 10 ND and 11 R/R patients (Table 1). Four had FCM-only involvement (2 ND, 2 R/R). Among these, the clonal population was 1.63% of WBC (range, 0.3-2.7%), and 3 had concurrent bone marrow (BM) or peripheral blood (PB) involvement. All 4 received intrathecal (IT) therapy. At median follow up of 23 months, 3 (75%) have died (2 from CNS disease progression, 1 unknown due to loss in follow up), and 1 remains alive in remission 44 months later following IT methotrexate (MTX) and CAR T-cell therapy. 17 had overt CNS disease (8 ND, 9 R/R). The clonal population was 9% (range, 0.2-98%). Eight (47%) had concurrent BM or PB involvement. Twelve (70%) received IV high dose MTX, and the remainder received only IT therapy. At median follow up of 42 months, 9 (53%) have relapsed (2 CNS only, 1 systemic, 6 both), and 9 have died. Median time to CNS relapse was 5 months. Conclusions: CSF 8 color FCM screening of DLBCL/HGBCL patients yields a low proportion of positive results, mostly in the setting of overt CNS disease. However, even FCM-only patients had poor outcomes (2/4 with CNS progression), suggesting that blood contamination does not explain CSF findings, and that these patients should be approached as secondary CNS involvement. Better pt selection for CSF screening is needed to reduce unnecessary LPs. Intensified or novel approaches for all FCM+ patients are needed.

PD-1 Blockade Combined with R-CHOP in Patients with Newly Diagnosed EBV-Positive Diffuse Large B-Cell Lymphoma: A Retrospective Analysis

Background Epstein-Barr virus (EBV) -positive diffuse large B cell lymphoma (EBV+ DLBCL) is a relatively rare aggressive B-cell lymphoma. Most patients present with advanced disease, high incidence of extranodal involvement of 30% to 80% (Keane, Eur J Haematol, 2019), as well as poor prognosis when treated with immunochemotherapy. However, no consensus on standard treatment has been established by now. It was found that the expression of programmed death ligand-1 (PD-L1) was increased in EBV+ DLBCL (Kim, Cancer Res Treat, 2019). In addition, chronic EBV infection results in T-cell exhaustion that can be reversed by PD-1 blockade. Compared with PD-L1-positive EBV-negative DLBCL cell lines, the application of PD-1 blockade in PD-L1-positive EBV+ DLBCL cell lines can significantly restore T cell proliferation and activity(Quan, PLoS One, 2015), suggesting that targeting the PD-L1/PD-1 pathway represents a potential therapy for EBV+ DLBCL. Therefore, we retrospectively analyzed the data of nineteen patients with EBV+ DLBCL who were treated with PD-1 blockade combined with RCHOP in our center, hoping to provide reference for subsequent research. Methods Eligible pts had treatment-naive histologically confirmed diagnosis of EBV+ DLBCL. Additional eligibility criteria included at least one measurable lesion, acceptable haptic and hematological function. Pts with primary CNS lymphoma, primary mediastinal large B-cell lymphoma, secondary CNS involvement were excluded. Additional exclusion criteria included history of immune system disease, uncontrolled infection. Once deemed eligible, pts will receive six cycles of RCHOP combined with PD-1 blockade(21 days per cycle) as induction therapy and subsequently maintenance with PD-1 blockade for 1 year(21 days per cycle). End of treatment(EOT) responses were assessed by PET-CT according to the Lugano Classification 2014. The primary objective was to assess the overall response rate(ORR) at EOT. Results Between May 1, 2019, and Sep 1, 2022, 19 pts were enrolled. Pts' baseline demographics, clinical and pathological characteristics are shown in Table 1. The median age was 64 years old without significant gender difference. The majority of pts were intermediate- to high-risk by IPI. EBV DNA can be detected in blood serum at diagnosis in more than half of all patients. No patient was diagnosed with double expressor lymphoma among 18 specimens that were detected c-Myc and BCL-2 with immumohistochemical staining. EBV-encoded RNA (EBER) was positive(&amp;gt;80% of the tumor cells) in all specimens. PD-L1 positivity(&amp;gt;10% of the tumor cells) or CD30 positivity(&amp;gt;5% of the tumor cells) was also quite common. Besides, no double hit lymphoma was confirmed in patient with Fluorescence situ hybridization test(n=13). Treatment course and efficacy evaluation of all pts are summarized in Figure 1. All patients enrolled in this study had completed 6 cycles of induction therapy. Totally, the ORR at EOT was 94.7%, and all achieved CMR. The ORR of patients with PD-L1 positivity(n=10) was numerically higher than that of patients with negative PD-L1 expression (n=5) (100% vs 80%). EBV DNA detected in blood serum of thirteen patients have decreased to undetectable level after induction therapy. The immune-related adverse events (irAEs) were emphatically analyzed. One patient had recurrent fever after every dose of PD-1 blockade without obvious evidence of infection. Another patient developed grade 3 diarrhea since the second cycle of PD-1 blockade maintenance. Colonoscopy showed mucosal swelling and multiple superficial ulcers in the whole colon, which indicated immune colonitis. Maintenance therapy was therefore discontinued. No irAE was observed in the rest of patients. With a median follow-up time of 13.1m (7.2-38.5m), the median PFS and OS were not reached. Both of 1 year OS and PFS was 89.5%. Overall, 2 pts experienced disease progression (1 at EOT, 1 at 2 months after ASCT), 2 pts died (1 due to progressive disease, 1 due to COVID-19 infection ). Conclusions PD-1 blockade combined with R-CHOP as induction therapy in patients with newly diagnosed EBV+ DLBCL has demonstrated satisfactory response and limited irAEs. Longer follow-up is still warranted to confirm the long-term benefit, especially for patients with maintenance of PD-1 blockade. Still, we believe this therapeutic strategy can be regarded as a successful attempt at improving prognosis for pts with EBV+ DLBCL.

Lisocabtagene Maraleucel (liso-cel) in Patients (Pts) with R/R MCL: Subgroup Analyses in Pts with High-Risk Disease Features from the MCL Cohort of the TRANSCEND NHL 001 Study

Background: Pts with R/R MCL after ≥ 2 prior lines of therapy, including a Bruton tyrosine kinase inhibitor (BTKi), have poor prognosis. Among pts with R/R MCL, several high-risk disease features are associated with a worse prognosis, including TP53 mutation, high proliferation index (Ki-67 ≥ 30%), blastoid morphology, and secondary CNS involvement. Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In the primary analysis of the MCL cohort from the phase 1, seamless design TRANSCEND NHL 001 study (NCT02631044), liso-cel treatment resulted in a rapid, high rate of durable CRs with a manageable safety profile in pts with heavily pretreated R/R MCL. Here we report the outcomes in pts with R/R MCL from prespecified subgroup analyses based on high-risk disease features. Methods: Eligible pts had PET-positive R/R MCL after ≥ 2 lines of prior therapy, including a BTKi, alkylating agent, and CD20-targeted agent. Pts received liso-cel at a target dose of 50 × 10 6 or 100 × 10 6 CAR + T cells after lymphodepleting chemotherapy. Bridging therapy was allowed. Primary endpoints were treatment-emergent AEs (TEAE) and ORR by independent review committee (IRC) per Lugano 2014 criteria; secondary endpoints included CR rate, duration of response (DOR), PFS, and OS. The liso-cel-treated set included all pts who received liso-cel. The efficacy analysis set included all pts in the liso-cel-treated set who had PET-positive disease per IRC at baseline. Results: Of 104 leukapheresed pts, 88 received liso-cel. Median on-study follow-up was 16.1 mo (range, 0.4-60.5). Median age was 68.5 y (range, 36-86) and median prior systemic lines of therapy was 3 (range, 1-11). Among liso-cel-treated pts, 66 (75%) had Ki-67 ≥ 30% and 15 (17%) had Ki-67 &amp;lt; 30% (Ki-67 was not reported in 7 [8%] pts); 20 (23%) had a TP53 mutation present and 34 (39%) did not ( TP53 mutation was indeterminate in 4 [5%] pts and not reported in 30 [34%] pts); and 27 (31%) had blastoid morphology and 48 (55%) did not (blastoid morphology was not reported in 13 [15%] pts). Most pts with these high-risk disease features also had disease that was refractory to last therapy, was refractory to prior BTKi, and had a complex karyotype. A total of 7 (8%) pts had secondary CNS lymphoma, of which 5 had refractory disease, 5 had Ki-67 ≥ 30%, and 1 each had TP53 mutation and blastoid morphology. Response rates, PFS, and OS across subgroups were consistent with the overall population, with high ORR and CR rate that was durable and high PFS and OS (Table 1). Although a limited number of pts had TP53 mutation assessed, pts with TP53 mutation had a numerically lower median DOR than the overall population, likely due to a higher proportion of objective responders achieving a PR than CR; however, pts with TP53 mutation who achieved CR had durable responses with 6 of 11 pts in an ongoing response at data cutoff. Among the 7 pts with secondary CNS lymphoma, response rates were high (ORR, 86% [n = 6]; CR rate, 71% [n = 5]), and 3 of 5 pts who achieved CR were in an ongoing response at data cutoff. Safety outcomes across subgroups were generally consistent with the overall population (Table 2). Most cytokine release syndrome (CRS) and neurological events (NE) were low grade in all subgroups, similar to the overall population (any-grade CRS, 61% [grade 3-4, 1%]; any-grade NEs, 31% [grade 3-4, 9%]; and no grade 5 CRS or NEs). Incidences of other TEAEs of special interest were also similar among subgroups. Of the 7 pts with secondary CNS lymphoma, 5 had low-grade CRS and 3 had low-grade NEs with no grade ≥ 3 CRS or NEs reported; 1 pt had a grade ≥ 3 infection. Cellular kinetics and B-cell aplasia by subgroup will be presented. Conclusions: In these subgroup analyses including pts with R/R MCL and high-risk disease features (Ki-67 proliferation index ≥ 30%, TP53 mutation, blastoid morphology, and secondary CNS lymphoma), liso-cel demonstrated clinically meaningful efficacy across subgroups with durable responses. Efficacy and safety outcomes were generally consistent with the overall study population. While some subgroups were limited by small numbers, these results suggest a favorable benefit/risk profile for liso-cel in pts with R/R MCL and high-risk disease features, a pt population for whom effective treatment options are rarely available.

Targeting EBV Encoded Viral Kinases with GCV, AZT, Rituximab and Dexamethasone (GARD) Results in Durable Responses in Patients with CNS Lymphoproliferative Disease

Introduction: Epstein-Barr virus positive (EBV+) central nervous system lymphoproliferative diseases (CNS-LPD) are aggressive clinical conditions with poor prognosis. EBV+ CNS-LPD often occurs in the setting of immune suppression and comorbidities (solid organ transplant, autoimmunity). Treatment with high-dose methotrexate has increased survival but is not a viable option for all patients, highlighting the need for alternative treatments. Previous research has reported EBV+ CNS-LPD exhibits unique genetic and immunobiological signatures, however, few studies have reported on the epigenetic landscape. We have previously reported use of ganciclovir (GCV), zidovudine (AZT), rituximab and dexamethasone (GARD) regimen induced complete and durable responses in a cohort of 13 patients with primary CNS post-transplant lymphoproliferative disease (PCNS-PTLD). Here we present 24 patients (10 from prior cohort and 14 new) with EBV+ CNS-LPD treated with GARD. We extend follow-up time for the previous cohort and add molecular context to clinical observations. We performed DNA methylation and expression analysis of EBV viral kinases in available tumor samples and revealed unique viral epigenetic states leading to expression of antiviral drug targets in an array of EBV+ CNS-LPD. Methods: We conducted an IRB-approved, retrospective review of patients with EBV+ CNS-LPD treated with GARD at The Ohio State University Wexner Medical Center between 1998-2022. Patient information was extracted from the electronic medical record. Treatment consisted of two-week induction of twice daily IV GCV/AZT (5mg/kg and 1,500 mg) IV dexamethasone (10-40mg), and weekly rituximab (375mg/m 2). After induction, dexamethasone was tapered, and GCV/AZT was switched to maintenance oral dosing of 450mg valganciclovir twice daily and 300mg of AZT twice daily. Rituximab was administered on days 1, 8, 15, and 22. Two-year overall survival (OS), five-year OS, and overall response rate were assessed. Available CNS-LPD biopsy samples were obtained, and expression of EBV lytic genes BZLF1, BXLF1 (thymidine kinase), and BGLF4 (protein kinase) were measured via qRT-PCR. Mass spectrometry based EpiTYPER assay was used to report the percentage of DNA CpG methylation in the gene promoters for viral BZLF1, BXLF1, BGLF4 and LMP1 genes . Biopsies from 17 patients with systemic PTLD with no CNS involvement were used for comparison. Results: 24 patients with EBV+ CNS-LPD were identified. 21 (87.5%) patients were diagnosed with a primary CNS-LPD (PCNS-LPD). Of the PCNS-LPD, 14 patients were PCNS-PTLD, 4 were receiving immunosuppression for autoimmune conditions, 1 patient had type 2 diabetes and two had no known history of immunosuppression. The remaining three patients had systemic PTLD with secondary CNS involvement. Diffuse large B-cell lymphoma was the most common histology (11; 45.8%) followed by grade 3 lymphomatoid granulomatosis (5; 20.8%), B-cell LPD (5;20.8%), polymorphic PTLD (2;8.3%) and one large cell lymphoma of ambiguous lineage. All patients were HIV negative. EBER was positive in all biopsies and EBV PCR of cerebrospinal fluid was positive in patients without biopsy. Sixteen patients (66.7%) achieved a completed response, with an overall response rate of 83%. Two-year OS was 62.5% (95% CI, 45.8-85.2%) and five-year OS was 52.8% (95% CI, 35.7%-77.9%). Five CNS-LPD brain biopsies were available for analysis. qRT-PCR of biopsy specimens showed expression of LMP1, BXLF1, and BGLF4, but not BZLF1. Expression of BGLF4 was significantly higher (p=1.35e-5) in CNS-LPD when compared to systemic EBV+ PTLD. EpiTYPER data showed significantly decreased promoter methylation for viral kinases BXLF1 and BGLF4 (p=0.0281 p=0.0089). Conclusions: We have shown that GARD regimen shows efficacy in the treatment of EBV+ CNS-LPD, with 62.5% two-year OS and 52.8% five-year OS. Our results provide the molecular basis for expression of lytic viral kinases BXLF1 and BGLF4 in CNS-LPD by showing that both genes exhibit decreased promotor methylation. This expression of viral kinases in CNS-LPD supports the mechanistic rationale of this antiviral approach and could be further investigated as a predictive biomarker. Overall, this research highlights unique epigenetic features of EBV in CNS-LPD that support the use of antiviral, specifically the GARD regimen, in EBV+ CNS-LPD.

Efficacy of Lisocabtagene Maraleucel for Relapsed or Refractory Aggressive B Cell Lymphoma in Our Hospital

[Background] Although the standard treatment for relapsed or refractory large B-cell lymphoma (LBCL) is high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT), the prognosis of relapsed or refractory LBCL is poor. The chimeric antigen receptor (CAR) T-cell therapy showed efficacy against relapsed or refractory LBCL. However, little real-world data on lisocabtagene maraleucel (liso-cel) were reported. Therefore, we report our data on liso-cel for relapsed or refractory LBCL in our institution. [Methods] We retrospectively analyzed clinical characteristics of patients who underwent leukapheresis to manufacture liso-cel between August 2021 and March 2023 at Toranomon Hospital. Overall survival (OS), progression-free survival (PFS), and duration of response (DOR) were calculated using the Kaplan-Meier method. OS was defined as the time from infusion of liso-cel to the date of death or last follow-up. PFS was defined as the time from infusion of liso-cel to progression of disease or death. DOR was defined as the time from first complete response or partial response to disease progression or death. The Cox proportional hazards model was used to determine the significance of multiple variables. [Results] Leukapheresis for the manufacture of liso-cel was performed in 25 cases. Of these 25 cases, liso-cel could not be manufactured in only one patient, and the other 24 patients received liso-cel infusion. Of the 24 patients who received liso-cel, 14 were men and the median age was 64.5 years (range, 29-78). Twenty-one patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; the other 3 had a PS of 2. The other clinical characteristics were as follows: Stage III/IV in 21 (87.5%); Bulky mass in 6 (25%); extranodal involvement &amp;gt; 1 in 9 (38%); international prognostic index (IPI) &amp;gt; 2 in 13 (54%); and elevated LDH in 11 (46％). Histological diagnoses were diffuse large B-cell lymphoma (n=13), transformed follicular lymphoma (n=6), primary mediastinal large B-cell lymphoma (n=3), and high-grade B-cell lymphoma (n=2), respectively. Secondary central nervous system (CNS) involvement was detected in 4 cases. The number of patients with primary refractory disease or relapse within 12 months after first-line chemotherapy is 10 (42%) and 10 (42%), respectively. Since 10 patients with primary refractory disease required immediate chemotherapy until leukapheresis was performed, liso-cel was used as a third-line or later in all cases. Patients had received a median of 4 (range, 2-9) previous lines of chemotherapy. Six patients (25%) had received a previous autologous HSCT, and two (8%) had received a previous allogeneic HSCT, respectively. The median time from leukapheresis to liso-cel arrival at our institution was 42 (range, 37-45) days. Bridging chemotherapy after leukapheresis was performed in all cases, with polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) being the most common with 13 cases (54%). Eight cases (33%) had achieved complete response (CR), and 8 cases (33%) had achieved partial response (PR) before lymphodepleting chemotherapy. The median follow-up of survivors was 7.7 months (range, 2.5-14.5). The median OS, PFS, and DOR were 11.5 months (95% confidence interval [CI]: 8.9 to not applicable, NA), 8.5 months (95% CI: 2.1 to NA), and 8.9 months (95% CI: 3.3 to NA), respectively. The overall response rate was 71%, with 54% achieving CR. Cytokine release syndrome (CRS) and neurological events (NEs) occurred in 21 (88%) and 2 patients (8%); grade 3 or worse CRS and NEs occurred in 1 (4%) and 2 patients (8%). Grade 3 or worse neutropenia, anemia, and thrombocytopenia were occurred in 23 (96%), 14 (50%), and 17 cases (71%), respectively. Prolonged Grade 3 or worse neutropenia was seen in 12 cases (50%) at 28 days after liso-cel infusion. No treatment-related death was not observed. Six patients died, and the causes of death were LBCL (n=3), pneumonia (n=2), and COVID-19 (n=1). In the multivariate analysis, independent risk factors for PFS were PS of 2 (hazard ratio [HR], 56.39; 95% CI, 8.31 to 382.7; p&amp;lt;0.001) and disease status (stable disease/progressive disease) before lymphodepleting chemotherapy (HR, 6.14; 95% CI, 1.07 to 35.06; p=0.04). [Conclusion] In our cohort, liso-cel has shown high response in relapsed or refractory LBCL. Disease status before lymphodepleting chemotherapy is significant for better prognosis.

Lisocabtagene Maraleucel in Relapsed/Refractory Large B-Cell Lymphoma: Real World Analysis from the Cell Therapy Consortium

Introduction Lisocabtagene maraleucel (liso-cel) is an autologous CD19-directed CAR T cell therapy approved for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) based on the TRANSCEND (Abramson et al, Lancet 2020), TRANSFORM (Kamdar et al, Lancet 2022), and PILOT studies (Sehgal et al, Lancet Oncol 2022). Extending clinical trial results for liso-cel to the real-world setting, we performed a multicenter retrospective study to evaluate the safety and efficacy of liso-cel in standard of care practice. Methods Patients (pts) aged ≥18 years with LBCL who received commercial liso-cel infusion between February 2021 (time of FDA approval) and June 2023 at 7 academic US medical centers were identified from the Cell Therapy Consortium registry. Pt and treatment characteristics were summarized descriptively, and the Kaplan Meier method was used for survival outcomes. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT consensus criteria. Tumor response was assessed per Lugano criteria locally by the treating clinician. Results As of 6/10/2023, 101 pts underwent liso-cel infusion. Detailed baseline pt characteristics are shown in Table 1. Median age at apheresis was 71 years (range: 30-85) with 35% of pts ≥75 years, 60% were male, 16% had an ECOG PS of ≥2 at apheresis, and 11% had active secondary CNS involvement. By histology, 86% of pts had DLBCL, 7% HGBL, 5% TFL, and 2% PMBCL. Baseline comorbidities included diabetes (18%), stage IV chronic kidney disease (5%), cerebrovascular disease (5%), impaired cardiac ejection fraction (2%), pulmonary dysfunction (2%), impaired hepatic function (2%), and active infection (3%), with 68% having a Charlson Comorbidity Index score of ≥3. Due to comorbidities, 30% of pts would have been ineligible for the TRANSCEND clinical trial. The median number of prior therapies was 3 (range: 1-8) and 16% of pts underwent prior autologous stem cell transplant. Bridging therapy was used in 62% of pts including 41% receiving polatuzumab-based treatment, 24% chemoimmunotherapy, and 21% radiation therapy. Seven (7%) pts received liso-cel on an expanded access trial (NCT04400591) due to a non-conforming product. Median time from apheresis to CAR T-cell infusion was 39 days (IQR: 34-43) and 85% of CAR T-cell infusions occurred inpatient. Any Grade CRS occurred in 49% (3% were Grade ≥3) and any Grade ICANS occurred in 26% (10% were Grade ≥3). Median onset of CRS and ICANS was 4 and 6 days following liso-cel infusion, respectively. Tocilizumab was administered in 31% and 31% of pts received steroids for toxicity management. Nine deaths (9%) unrelated to lymphoma progression occurred at a median of 1.2 months (range: 0.3-4.3) with 2 due to infectious complications, 2 due to other malignancy, 1 due to grade 5 neurologic toxicity, 1 due to concurrent grade 5 neurologic toxicity and grade 5 CRS, 1 due to accidental death, and 2 due to unknown causes. The 6-month incidence of non-relapse mortality was 8% (95% CI, 3.4% - 15%). The overall response rate (ORR) to bridging therapy, as assessed prior to lymphodepletion, was 45% with 17% achieving a complete response (CR). Following liso-cel infusion, response assessment was performed at day 30 and/or day 90 according to treating center practice, or in those determined to have clinical progression. Of the 89 pts evaluable at day 30, the ORR was 81% with 63% achieving a CR. Among 76 pts evaluable at day 90, the ORR was 63% with 58% achieving a CR. With a median follow-up of 10.3 months (range 0.3-22.8), month 6 outcomes were 62.7% (95% CI, 52.8% - 74.3%) for progression-free survival, 71.6% (95% CI, 60.9% - 84.1%) for duration of response, and 77.1% (95% CI, 68.4% - 86.9%) for overall survival ( Figure 1). Conclusions These analyses confirm that efficacy and safety are similar or superior to those of patients enrolled in liso-cel prospective clinical trials for R/R LBCL. Notably, these outcomes were achieved in pts predominately of advanced age and with a significant comorbid burden, recognizing that one-third would have been ineligible for TRANSCEND. These results also likely reflect advancements in patient selection and toxicity management including the real world utilization of novel bridging therapy to temporize and debulk disease. Follow-up is ongoing and updated data will be presented at the meeting.

The Mini-Teddi-R Treatment Demonstrated a High Rate of Remission in Patients with DLBCL Involving the CNS Who Had Previously Been Exposed to BTK Inhibitors

Background: Secondary CNS B-cell lymphomas (SCNSL) are aggressive lymphomas with a bleak prognosis. TEDDI-R has been successful in achieving lasting remission in relapsed/refractory primary DLBCL of the CNS (PCNSL), but the effectiveness of ibrutinib-responsive tumors in SCNSL remains unknown. This study presents initial findings from the use of mini-TEDDi-R in SCNSL. Methods: Efficacy and safety data of mini-TEDDi-R were retrospectively analyzed for patients with DLBCL involving the CNS. All patients experienced relapse in the CNS or/and peripheral region after initial therapy. Brain parenchyma involvement allowed for treatment with MTX, Ara-c, and/or BTK inhibitors. The dosage of the drugs used in the original regimen was reduced, leading to the adoption of the term “mini-TEDDi-R.” Each 21-day cycle involved the following treatments: intravenous rituximab at a dose of 375 mg/m 2/day on days 1-2, oral temozolomide at a dose of 150 mg/m 2/day on days 2-5, intravenous infusion of 30 mg/m 2/day etoposide on days 2-5, intravenous infusion of 25 mg/m 2 of pegylated liposomal doxorubicin on day 2, intravenous infusion of dexamethasone at a dose of 10 mg/m 2/BID on days 1-5, and oral zanubrutinib at a dose of 200mg/BID or oral orelabrutinib at a dose of 150mg/qd or oral ibrutinib at a dose of 560mg/qd from day 1 until neutrophil count &amp;lt;0.5*10^9/L or platelet count &amp;lt;30*10^9/L. Additionally, intrathecal administration of 70 mg of cytarabine occurred on days 1 and 5, All remissions observed on MRI were confirmed through FDG-PET and CSF analysis. Results: Between December 2019 and June 2023, 24 patients with a median age of 53 (range 28-69) received mini-TEDDi-R treatment. All patients had DLBCL, comprising 16 (66.7%) non-GCB, 6 (25%) GCB, and 2 (8.3%) transformed from FL. All patients experienced relapse in the CNS system after a median of 6 (range 1-17) prior therapies, and all (100%) patients received prior anthracycline treatment. A total of 21 patients (87.5%) had received multiple lines of therapy before mini-TEDDi-R. Among them, 19 patients (79.2%) had received HD-MTX based salvage therapy, 11 patients (45.8%) had received HD-Ara-c based salvage therapy, and 14 patients (58.3%) had been exposed to BTK inhibitors. Seven patients (29.2%) showed triple resistance to MTX, Ara-c, and BTK inhibitors. Six patients had previously undergone transplantation, and four patients had experienced failure of CD19 CART treatment. Thirteen patients (54.2%) had isolated CNS disease, while 11 patients (45.8%) had both CNS and peripheral disease. Thirteen patients (54.2%) underwent 1 cycle of mini-TEDDi-R, 8 patients (33.3%) completed 2 cycles, 2 patients (8.3%) finished 3 cycles, and 1 patient (4.2%) completed 4 cycles. The objective remission rate (ORR) was determined to be 70.8%, with a complete remission (CR) rate of 58.3%. Notably, patients (N=14) exposed to BTK inhibitors previously exhibited a similar CR rate compared to patients (N=10) who had not received prior BTK inhibitor treatment (50% vs. 70%, p = 0.348). Patients (N=19) who had undergone HD-MTX based salvage therapy achieved an ORR of 74% and a CR rate of 58%. No significant difference in response rate was observed between patients with peripheral and non-peripheral secondary CNS involvement. In patients who achieved complete remission, only one patient experienced a second CNS relapse. Four patients bridged to auto-HSCT, 2 patients bridged to CART treatment, and 4 patients underwent auto-HSCT combined with CART treatment for consolidation. The median overall survival and median PFS have not been reached within the 11.8-month follow-up period. Toxicity was evaluated over 39 cycles. Grade 3 and 4 neutropenia occurred in 51% and 16% of cycles, respectively, while febrile neutropenia was observed in 10% of cycles. The median duration of neutropenia was 6 days (range 4-10). Three cycles (8%) were complicated by infections graded as ≥G3, but no opportunistic infections (including Aspergillus) were observed. Grade 3 and 4 thrombocytopenia occurred in 26% and 14% of cycles, respectively. The median duration of neutropenia was 7 days (range 3-14). Conclusions: The mini-TEDDi-R regimen demonstrated a favorable remission rate in patients with DLBCL involving the CNS. The treatment was well-tolerated, and patients with tumors that were previously exposed to BTK inhibitors and HD-MTX treatment also showed positive responses to mini-TEDDi-R.

Intent to Treat Allogeneic Stem Cell Transplantation Outcomes in Relapsed/Refractory T-Cell Lymphomas

Introduction T-cell lymphomas (TCL) are a heterogeneous group of lymphoproliferative malignancies with an overall poor prognosis. Despite aggressive first-line therapy, most patients experience disease relapse or progression. Allogeneic stem cell transplant (AlloSCT) is a standard of care for relapsed/refractory (R/R) TCL. However, many patients do not receive this potentially curative therapy. There is a paucity of data regarding the frequency of and barriers to undergoing AlloSCT in R/R TCL. To address this knowledge gap, we conducted a retrospective analysis of R/R TCL patients intending to undergo AlloSCT and hypothesized the primary barrier to AlloSCT to be lack of effective disease control. Methods We identified patients with a primary diagnosis of R/R TCL seen at the University of Washington/Fred Hutchinson Cancer Center (UW/FHCC) between 1/2008 and 6/2023 and linked these patients with the UW/FHCC bone marrow transplant (BMT) database to identify those who were intended for transplant. Intention to transplant (ITT) was defined as undergoing human leukocyte antigen (HLA) typing for purposes of AlloSCT. Patients with T-cell lymphoblastic leukemia/lymphoma were excluded. The primary endpoint was the rate of patients who underwent AlloSCT. Secondary endpoints included progression-free (PFS) and overall survival (OS) in patients who underwent AlloSCT and specific barriers to AlloSCT. Results Overall, 163 patients met ITT criteria. Males comprised 66% of patients. Median age was 65 (range 34-81) years and the median number of treatment regimens prior to HLA typing was 3 (range 1-10). The majority of patients (60%) were non-Hispanic whites (NHW), with Asians/Pacific Islanders (API), Hispanics/Latinos (HL), African Americans (AA) and Alaskan Natives/American Indians (ANAI) contributing 17%, 12%, 7% and 4%, respectively. Sixty-four patients (39%) had peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), 23 (14%) had angioimmunoblastic TCL (AITL), 17 (10%) had anaplastic large cell lymphoma (ALCL; 6 with ALK+), 16 (10%) had NK/TCL, 11 (7%) had hepatosplenic TCL, 12 (7%) had T-cell prolymphocytic leukemia, 5 (3%) had adult T-cell leukemia/lymphoma and 12 (7%) had primary cutaneous TCL. Twenty-two (13%) patients had secondary CNS involvement and 27 (17%) had previous autologous stem cell transplant. Of all patients who received HLA typing, 154 (94%) had a transplant consult, 54 (33%) initiated pre-AlloSCT workup and 51 (31%) underwent AlloSCT. Barriers to AlloSCT included progressive disease, patient preference, inability to identify a donor, indolent disease, poor functional status/multiple comorbidities and lack of a caregiver in 55%, 9%, 8%, 5%, 3% and 1%, respectively (Figure 1A). Six (5%) patients are currently receiving salvage therapy with plans for subsequent AlloSCT. AlloSCT occurred in NHW, API, HL, AA and ANAI patients at rates of 35%, 11%, 26%, 36% and 50%, respectively. All patients who were unable to undergo transplant due to lack of a donor were from groups other than NHW. AlloSCT rates were 30%, 39% and 17% in PTCL-NOS, AITL and ALCL, respectively. At a median follow-up time of 24.2 months, 101 (63%) patients are deceased with 83 (82%) due to disease. Twenty (39%), 17 (33%), 11 (22%) and 3 (6%) patients received an AlloSCT with a matched unrelated, matched related, mismatched unrelated and haploidentical donor, respectively. Fifteen (29%) patients underwent a myeloablative while 36 (71%) underwent a reduced intensity conditioning regimen. None of the 51 patients who underwent AlloSCT had pre-transplant measurable disease. Of transplanted patients, median PFS was 55.7 months and OS was 62.4 months (Figure 1B). Sixteen (31%) patients had eventual disease relapse. Eighty percent of relapses occurred within 3 months after AlloSCT. Seven (13%) and 6 (12%) of the transplanted patients were deceased within 12 months after AlloSCT due to disease relapse and complications of AlloSCT, respectively. Conclusions Although AlloSCT may be highly effective for R/R TCL achieving a CR, only a small minority of patients are able to undergo AlloSCT and the outcomes for the ITT population is dismal. Common barriers to undergoing AlloSCT include progressive disease and inability to identify suitable donors, particularly in minority populations. More effective pre-transplant salvage therapies and alternative AlloSCT donors are greatly needed.

Intravenous IL-1 Receptor Antagonist for Prevention of Severe Immune Effector Cell-Associated Neurotoxicity Syndrome

Background and Significance: The management of toxicities from autologous CD19-directed chimeric antigen receptor (CAR) T cell therapy have evolved and the rates of severe cytokine release syndrome (CRS) have declined from nearly 50% in early trials to 8% (CRS grade 3 or higher) from real-world retrospective data with axicabtagene ciloleucel (axi-cel) (Jacobson et al. TCT 2022). However, the rate of severe immune effector cell-associated neurotoxicity (ICANS) has only marginally improved since CAR-T cell therapy has become commercially available. With expanding indications for CAR-T cell therapy, the prevention and management of ICANS remain an unmet need. We previously conducted a pilot, investigator-sponsored phase II study using Anakinra, an IL-1 receptor antagonist, administered subcutaneously at the onset of grade 2 CRS or any grade ICANS (Oliai et al. ASCO 2021) which demonstrated that anakinra is safe and feasible. There are several prospective studies that are currently open to accrual that incorporate subcutaneous Anakinra for prevention and treatment of severe ICANS (NCT04359784, NCT04148430, NCT04150913, and NCT04432506). Anakinra crosses the blood brain barrier and has been shown to be safe and efficacious in rheumatologic conditions. Relatively high doses of IV Anakinra have been shown to be safe in severe sepsis and in subarachnoid hemorrhage. We hypothesize that IV Anakinra is safe and effective in preventing severe ICANS in patients undergoing standard of care axi-cel therapy for large B cell lymphoma. Study Design and Methods: This investigator-sponsored trial (NCT4205838) is a phase Ib/II study of adults eligible for standard of care axi-cel for large B cell lymphoma. Anakinra will be administered intravenously using a standard 3+3 design with cohort 1 receiving 200mg IV loading dose, followed by 100mg IV q6h maintenance dose and cohort 2 receiving 400mg IV loading dose, followed by 200mg IV q6h. The trigger to initiate Anakinra is any grade ICANS or grade ≥2 CRS in the absence of ICANS, based on ASTCT 2019 criteria. In addition to Anakinra, participants will receive standard of care interventions for CRS and ICANS. Subjects with secondary CNS involvement are included. Key exclusion criteria are primary CNS lymphoma, Burkitt's lymphoma, transformed DLBCL from CLL, prior allogeneic stem cell transplantation, &amp;lt; 30 days of exposure to immune check point inhibitor therapy. The study is open to accrual at University of California, Los Angeles (UCLA) with 2 additional sites within the University of California Hematologic Malignancies Consortium (UCHMC). Objectives: The primary objective is to evaluate the safety and tolerability of Anakinra given intravenously in patients undergoing CAR-T cell therapy and to estimate the efficacy of Anakinra in prevention of severe ICANS (grade ≥3). Secondary objectives include the impact of Anakinra on the efficacy of CAR-T cell therapy for large B cell lymphoma, the duration of ICANS, and the pharmacokinetics of Anakinra. Exploratory objectives focus on changes in inflammatory cytokines during ICANS in the peripheral blood. Statistics and Current Status: Using historical control from the real-world experience using axi-cel for relapsed/refractory large B-cell lymphoma (38%, Jacobson et al. ASH 2018), a sample size of 36 patients achieves 80% power to detect a 50% reduction in the rate of severe ICANS when comparing to the historical control using a one-sample exact binomial test at the two-sided type I error rate of 0.10. This study has been open at UCLA since February 2023. Two of 4 enrolled participants met criteria to receive IV Anakinra. Conclusions: The safety and tolerability of IV Anakinra is being evaluated in patients with large B cell lymphoma undergoing treatment with axi-cel in order to prevent severe ICANS.

POSTER: ABCL-269 Secondary Central Nervous System (CNS) Involvement in Diffuse Large B Cell Lymphoma (DLBCL): Ten-Year Outcomes From Mexico's National Cancer Institute

POSTER: ABCL-269 Secondary Central Nervous System (CNS) Involvement in Diffuse Large B Cell Lymphoma (DLBCL): Ten-Year Outcomes From Mexico's National Cancer Institute

ABCL-269 Secondary Central Nervous System (CNS) Involvement in Diffuse Large B Cell Lymphoma (DLBCL): Ten-Year Outcomes From Mexico's National Cancer Institute

ABCL-269 Secondary Central Nervous System (CNS) Involvement in Diffuse Large B Cell Lymphoma (DLBCL): Ten-Year Outcomes From Mexico's National Cancer Institute

Clinical efficacy and safety of chimeric antigen receptor T-cell therapy for mantle cell lymphoma with secondary central nervous system involvement.

Data describing outcomes of chimeric antigen receptor (CAR) T-cell therapy in patients with secondary central nervous system (SCNS) involvement of mantle cell lymphoma (MCL) are limited. We identified 10 patients with MCL and SCNS involvement treated with anti-CD19 CAR T-cell therapy at three US academic centres. Frequent objective responses were observed in the CNS (86%) and systemically (90%), and the 1-year progression-free survival was 47%. Seven patients developed immune-effector-cell-associated-neurotoxicity-syndrome (n = 2 Grade 1, n = 5 Grade 3). Our results suggest that anti-CD19 CAR T-cell therapy in this setting is feasible and additional data regarding neurotoxicity in this population may be warranted.