Toxicities and outcome after <scp>CD19</scp>‐directed chimeric antigen receptor T‐cell therapy for secondary neurolymphomatosis
Authors: Leon D. Kaulen, Philipp Karschnia, Sofia Doubrovinskaia, Jeremy S. Abramson, Maria Martinez‐Lage, Ganesh Shankar, Bryan D. Choi, Jeffrey A. Barnes, Areej El‐Jawahri, Ephraim P. Hochberg, P. Connor Johnson, Jacob D. Soumerai, Wolfgang Wick, Marcela V. Maus, Yi‐Bin Chen, Matthew J. Frigault, Jorg Dietrich
Journal: American Journal of Hematology (2024)

Lymphomatous infiltration of the peripheral nervous system (PNS), termed neurolymphomatosis, represents a distinct extranodal non-Hodgkin lymphoma variant with dismal outcome. CD19-directed chimeric antigen receptor (CD19-CAR) T-cell therapy has emerged as a safe and effective treatment for B-cell lymphomas. We aimed to assess toxicity and efficacy of CD19-CAR T-cells in neurolymphomatosis. Neurolymphomatosis patients treated with CD19 CAR T-cells were retrospectively identified at Massachusetts General Hospital over a six-year period. Toxicities were graded according to the ASTCT classification, management, and response rates were recorded. Eleven neurolymphomatosis patients were identified with a median of 2 lines of PNS-directed treatments (range: 1-3) prior to receiving CD19-CAR T-cells. Neurolymphomatosis localized to the nerve roots (8/11, 73%), plexus (5/11, 45%), peripheral (4/11, 36%) and cranial nerves (5/11, 45%). Low grade cytokine release syndrome (CRS) was detected in 8/11 (73%; grade 1: N = 7; grade 2: N = 1) cases. Low- and high-grade immune cell-associated neurotoxicity syndrome (ICANS) were recorded in 5/11 (45%; grade 1: N = 4; grade 2: N = 1) and 1/11 (9%; grade 4) patients, respectively. CRP levels at infusion were predictive of ICANS (area under the curve: 0.96, p = 0.01). Seven of eleven neurolymphomatosis patients (64%) responded to CD19-CAR T-cells. Complete remissions (CR) were achieved in three cases (27%), with 2 patients in sustained CR nine and 46 months after CD19-CAR infusion. Median progression-free survival (PFS) was 4 months. Collectively, CD19-CAR T-cell treatment was well tolerated and showed promising efficacy in recurrent neurolymphomatosis, a difficult to treat condition with unmet medical need. Findings suggest that CD19-CAR may sufficiently penetrate the blood-nerve barrier. Toxicity and outcomes were overall similar to CAR-T cell therapy in CNS lymphoma. Neurolymphomatosis (NL) refers to invasion of the peripheral nervous system (PNS) by neurotropic non-Hodgkin lymphoma (NHL).1-3 Given the unique disease distribution, NL is considered a distinct extranodal NHL variant.1-3 Successful systemic therapy requires penetration of the blood-nerve barrier, which protects the PNS, and is anatomically distinct from the blood-brain barrier. Reflecting the lack of clinical trials, no standard of care has been defined and outcome remains poor. Median overall survival was 10 months in a multicenter study conducted by the international primary CNS lymphoma collaborative group (IPCG), despite management with systemic high-dose methotrexate (HD-MTX, >3.5 g/m2) and rituximab-based chemotherapy.1 CD19-directed chimeric antigen receptor T cells (CD19-CAR) have transformed the treatment of systemic large B-cell lymphomas. Overall response rates of up to 80% in relapsed/refractory clinical trial populations led to the US Food and Drug Administration approval of several CD19-CAR products. Patients with nervous system disease were largely excluded from these trials due to concern for immune effector cell-associated neurotoxicity syndrome (ICANS). However, subsequent trials and real-world data have demonstrated comparable efficacy and safety for primary and secondary central nervous system (CNS) lymphomas.4-8 Here, we report our institutional experience of relapsed/refractory NL, a distinct nervous system NHL subtype with unmet medical need, treated with intravenous CD19-CAR at Massachusetts General Hospital between 2018 and 2024. Main objectives were PNS-specific efficacy and safety. Inclusion criteria were: (1) active NL diagnosed per neuroimaging or PNS biopsy, (2) CD19-CAR therapy, and (3) available follow-up neuroimaging. Exclusion criteria followed a previous IPCG study1: (1) Cranial nerve or cauda equina lesions when CSF involvement was present unless neuroimaging demonstrated intra- and extradural disease or additional PNS foci elsewhere. (2) Bulky disease with PNS entrapment. Cytokine release syndrome (CRS) and ICANS assessment and grading were prospectively performed during routine care following ASTCT guidelines.9 Neuroimaging performed pre-infusion served as baseline exam. Radiographic responses were assessed on magnetic resonance imaging (MRI) or 18-fluorodeoxyglucose positron emission tomography (FDG-PET) at one, three, six, and twelve months post CD19-CAR therapy as available. The interval from apheresis until administration of lymphodepleting chemotherapy was defined as bridging. To additionally evaluate responses to bridging therapy, neuroimaging at baseline, that is, at CD19-CAR infusion, was compared with studies obtained before bridging therapy. Given lack of formal response assessment criteria for NL, MRI evaluation followed IPCG criteria established for solid CNS disease.10 PNS response assessment on FDG-PET was based on the Lugano consensus classification.11 Progression-free survival (PFS) was calculated from CD19-CAR infusion to date of radiographic nervous system (PNS or CNS) progression or death from any cause. Patients lost to follow-up were censored. This retrospective study was approved by the Massachusetts General Hospital Institutional Review Board. We identified eleven secondary NL treated with CD19-CAR. Histological diagnoses were diffuse large B-cell lymphoma (DLBCL, 9/11, 82%), and transformed lymphoma from follicular or mantle cell lymphoma (each 1/11, 9%). Most DLBCL were classified as non-germinal-center B-cell like (8/9, 89%). Based on available MYC, BCL2, and BCL6 immunohistochemistry, 3/8 (38%) and 1/8 (13%) were double- and triple-expressor DLBCL, respectively. MYC, BCL2, BCL6 rearrangement indicated double-hit DLBCL in 1/7 (14%) cases. At CD19-CAR infusion, all patients had relapsed/refractory NL with a median three previous NHL treatments (range: 2–6). This included a median of two NL-directed lines of treatment (range: 1–3). After NL diagnosis, all patients had failed intravenous HD-MTX (8/11, 73%) or rituximab (6/11, 55%). At the time of CD19-CAR infusion, they were deemed ineligible for autologous stem cell transplant by treating physicians. Neurological examination at baseline was remarkable for painful asymmetric polyneuropathy (9/11, 82%) and cranial neuropathy (4/11, 36%). Median Karnofsky performance status was 80 (range: 50–90). Per MRI and FDG-PET, all patients had active, multifocal NL. Lesions localized to nerve roots (8/11, 73%), plexus (5/11, 45%), peripheral (4/11, 36%), and cranial nerves (5/11, 45%). NL was frequently accompanied by CSF involvement (5/11, 45%). Concurrent parenchymal CNS lesions were found in two (18%), while systemic disease outside the nervous system was present in five patients (45%). Patient characteristics are summarized in Tables S1 and S2. All patients underwent bridging therapy consisting of systemic chemotherapy (10/11, 91%) or involved field radiation therapy (5/11, 45%). Bridging chemotherapy included HD-MTX (4/11, 36%), rituximab, or bruton tyrosine kinase inhibitors (each 3/11, 27%). It achieved partial response (PR) in three (27%) and stable disease (SD) in five (45%) NL cases. Despite bridging therapy, disease progression (PD) occurred in three cases (27%). Lymphodepletion consisted of cyclophosphamide and fludarabine chemotherapy as per standard protocol. Commercially available CD19-CAR with 4-1BB (tisagenlecleucel: 6/11, 55%; lisocabtagene maraleucel: 3/11, 27%) or CD28z costimulatory domains (axicabtagene ciloleucel: 2/11, 19%) were infused. Following CD19-CAR infusion, CRS was detected in eight cases (73%, Figure 1A.), classified as low-grade (grade 1: 7/8; grade 2: 1/8), after a median of 3.5 days (range: 3–9). CRS lasted a median of 3 days (range: 1–4). ICANS developed in six patients (55%, Figure 1A.), with median onset after 5.5 days (range: 3–10). It included five low-grade (45%; grade 1: 4/5; grade 2: 1/5) and one high-grade (9%; grade 4) case, all of which were associated with CRS (Figure 1B.). Neurotoxicity was managed with steroids in all patients. Additionally, anakinra and siltuximab were administered in grade 4 ICANS. Symptoms were transient and ceased after a median of three days (range: 3–10). ICANS typically developed around peak serum C-reactive protein (CRP) and ferritin levels (Figure 1C,D). CRP levels at infusion were predictive of ICANS (area under the curve: 0.96, p = .01, Figure 1E). CRP >6 mg/dL predicted later ICANS development with 80% sensitivity and 100% specificity. Seven NL (64%) responded to CD19-CAR (Figure 1F,G) with complete (CR) and partial responses in three (27%) and four (36%) patients, respectively. Time to best response was one month in all complete responders. Two of three CR were sustained at the time of reporting, now 9 and 47 months after CD19-CAR. All radiographic responses (CR and PR) were associated with improvement of NL-related symptoms. This included improved pain (7/7), motor weakness (5/7), and sensory deficits (6/7). In the two cases with sustained CR, clinical remission lagged behind radiographic responses and was achieved after 6 and 12 months, respectively. Radiographic remissions were achieved irrespective of NL localization and included nerve root, plexus, and peripheral nerve lesions (Figure 1H). No apparent histological differences were noted between CD19-CAR responders and nonresponders (Table S3). A trend towards inferior KPS (Mann-Whitney test: p = .13) and higher LDH levels (Mann-Whitney test: p = .11) was found in nonresponders, who also did not respond to bridging therapy (0/4 vs. responders: 3/7, Fisher's exact test: p = .24). Median PNS-PFS in the entire cohort was four months. Radiographic disease progression was noted in seven patients. It involved the nervous system in all and the PNS in five including nerve root (N = 2), plexus (N = 1), cranial (N = 2), and peripheral nerve (N = 1) lesions. No treatment-related deaths were recorded. Our findings suggest that CD19-CAR may sufficiently penetrate the blood-nerve barrier, composed of microvascular endothelial cell tight junctions within the endoneurium,12 and are active in NL even in the absence of systemic disease elsewhere. This is noteworthy as no surrogate parameter for blood-nerve barrier trafficking of CD19-CAR exists in contrast to the blood-brain barrier, where CSF can be studied. However, many initial radiographic responses remained short-lived, and combination or consolidation treatments are warranted. To our knowledge, ORR in relapsed/refractory NL has not been reported. However, in the first line setting, a 77% ORR, including CR in 24%, was recently reported in a selected (≥24 months follow-up after NL diagnosis) patient population.3 Considering active, relapsed/refractory NL in transplant-ineligible patients, who had previous treatment failure to HD-MTX and rituximab, CD19-CAR ORR (64%) in our NL cohort was encouraging. However, the CR rate (27%) was lower than previously reported for CD19-CAR treated CNS lymphomas.4-8 In this regard, it was noteworthy that many included cases were refractory to previous treatments and typically (73%) lacked responses to bridging therapy, a well-established negative prognostic factor.7, 13 Prior reduction of NL disease burden or CD19-CAR administration in earlier stages, for example, the second-line setting, could additionally enhance the efficacy in NL. CD19-CAR treatment in NL was well-tolerated, and toxicity rates parallel previous B-cell lymphoma cohorts with and without CNS involvement.4-7 Like in systemic lymphomas, ICANS was closely associated with CRS and typically occurred in the context of systemic inflammation indicated by elevated serum CRP and ferritin levels.14 Notably, baseline CRP allowed to identify neurolymphomatosis patients, who later developed ICANS. This may have important implications for management and further supports CRP as a predictive biomarker for ICANS. Limitations include the retrospective design, but a prospective study appears unlikely given NL rarity. Analyses are limited by cohort size for similar reasons and the use of bridging treatments. Collectively, CD19-CAR were well-tolerated with similar toxicity profiles compared to previous cohorts with or without CNS involvement. Considering active disease and failure of systemic treatments, response rates were encouraging and suggest CD19-CAR may cross the blood-nerve barrier with activity even in the absence of systemic disease elsewhere. LDK, PK, MJF, and JD involved in data collection. LDK, SD, MF, and JD involved in data analysis and interpretation. LDK and JD involved in statistics. LDK, MJF, and JD involved in manuscript drafting. LDK, PK, SD, JSA, MML, GS, BDC, JAB, AEJ, EPH, PCJ, JDS, WW, MVM, YBC, MJF, and JD involved in manuscript revising. LDK and JD involved in study concept and design. Dr. L. D. Kaulen reports consulting fees and from Ono Pharmaceutical. Dr. P. C. Johnson reports consulting fees from Abbvie, AstraZeneca, ADC Therapeutics, Seagen, and research support from Incyte, Bristol Myers Squibb, AstraZeneca, Medically Home. Dr. J. Soumerai reports consulting fees from AstraZeneca, Bristol Myers Squibb, Genentech/Roche, and LOXO@Lilly, research support for investigator-initiated trials paid to the institution from Adaptive Biotechnologies, BeiGene, BostonGene, Genentech/Roche, GlaxoSmithKline, Moderna, Takeda, and TG Therapeutics. Dr. W. Wick reports consulting fees from Enterome, GSK, Roche, and Servier. Dr. M. J. Frigault reports consulting fees and research support from Brsitol Myers Squibb, Arcellx, Kite/Gilead, Jnj/Legend, Novartis, and Cytoagents. Dr. J. Dietrich reports consulting fees from Amgen, Novartis, Johnson & Johnson, SageMedic, and royalties from Wolters Kluwer. All remaining authors have declared no conflicts of interest. The authors confirm that the data supporting the findings presented are available in the article and the accompanying supplemental content. Requests for additional data should be sent to [email protected]. All data shared will be de-identified. Supplementary Table S1. Individual patient data. Supplementary Table S2. Baseline NL patient characteristics at CD19-CAR infusion. Supplementary Table S3. Radiological and pathological characteristics in responders and nonresponders. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.