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CD19-directed chimerical antigen receptor T-cell (CAR-T) products have gained US Food and Drug Administration approval for systemic large B-cell lymphoma. Because of concerns about potential immune cell-associated neurotoxicity syndrome (ICANS), patients with primary central nervous system (CNS) lymphoma (PCNSL) were excluded from all pivotal CAR-T studies. We conducted a phase 1/2 clinical trial of tisagenlecleucel in a highly refractory patients with PCNSL and significant unmet medical need. Here, we present results of 12 relapsed patients with PCNSL who were treated with tisagenlecleucel and followed for a median time of 12.2 months (range, 3.64-23.5). Grade 1 cytokine release syndrome was observed in 7/12 patients (58.3%), low-grade ICANS in 5/12 (41.6%) patients, and only 1 patient experienced grade 3 ICANS. Seven of 12 patients (58.3%) demonstrated response, including a complete response in 6/12 patients (50%). There were no treatment-related deaths. Three patients had ongoing complete remission at data cutoff. Tisagenlecleucel expanded in the peripheral blood and trafficked to the CNS. Exploratory analysis identified T-cell, CAR T, and macrophage gene signatures in cerebrospinal fluid following infusion when compared with baseline. Overall, tisagenlecleucel was well tolerated and resulted in a sustained remission in 3/7 (42.9%) of initial responders. These data suggest that tisagenlecleucel is safe and effective in this highly refractory patient population. This trial was registered at www.clinicaltrials.gov as #NCT02445248., (© 2022 by The American Society of Hematology.)

Allogeneic hematopoietic SCT (HSCT) can ideally provide long-term remission in advanced lymphoma patients by capturing a graft-vs-tumor (GVT) effect. On the basis of a murine model, we attempted to optimize a GVT effect through nonmyeloablative therapy and HLA-matched related donor HSCT with intentional induction of mixed chimerism followed by prophylactic donor lymphocyte infusion. A total of 26 advanced lymphoma patients were separated into an early and late full-donor chimerism (FDC) group using a median of 45 days post-HSCT as the defining point for FDC. Upon generating these groups, analysis by Student's t-test demonstrated that they were statistically distinct in time to develop FDC (P<0.01). There was a trend toward improved CR rates in the late group relative to the early group (62 vs 31%; P=0.12). A trend toward improved progression-free survival at 5 years was also observed in the late compared to the early group by Kaplan-Meier analysis (38 vs 8%; P=0.081). However, this did not correlate to a significant overall survival benefit. In conclusion, these data support the observation from our mouse models that the most potent GVT effect occurs in mixed chimeras with late chimerism conversion.

A 51-year-old patient with refractory non-Hodgkin lymphoma (NHL) received non-myeloablative conditioning and a two of six (A, B, DR) human leucocyte antigen (HLA) mismatched donor BMT. Post-BMT lymphocytes showed fluctuating T- and natural killer (NK)-cell chimerism, which culminated in mainly donor lymphocytes by Day + 100. Changes in lymphocyte chimerism correlated with anti-donor and anti-host responses in mixed lymphocyte reaction (MLR). On Day + 100, a strong anti-host response was observed in MLR in the absence of graft-versus-host disease (GVHD), together with near complete regression of the patient's lymphoma. A mild chronic GVHD later developed and, eventually, by 680 days post-BMT, the lymphoma had relapsed and MLR reflected a state of global immune unresponsiveness. These observations demonstrate evolving host-versus-graft and graft-versus-host tolerance that correlates with fluctuating lymphoid chimerism and graft-versus-lymphoma (GVL) effects, in the absence of severe GVHD. Eventual lymphoma relapse temporally correlated with a generalised immunosuppressed state.

We retrospectively reviewed our experience with the fine-needle aspiration biopsy (FNAB) diagnosis of primary and recurrent lymphoma to assess the ability of cytomorphology with and without ancillary flow cytometry (FCM) analysis to diagnose and subclassify these tumors according to the Revised European-American Lymphoma/World Health Organization classifications. We reviewed 139 consecutive FNABS of 84 primary and 55 recurrent lymphomas. FCM was successful in 105 (75%) cases. The overall results, including cases without FCM, included 93/139 (67%) true positive, 7 (5%) false negative, and 39 indeterminate (27 [19%] suspicious and 12 [9%] atypical) diagnoses of lymphoma. In cases with FCM, there were 80/105 (77%) true positive, no false negative, and 25 indeterminate diagnoses (15 [14%] suspicious and 10 [9%] atypical). The overall results of the 84 primary lymphomas were 55 (67%) true positive, 5 (5%) false negative, and 24 indeterminate (14[16%] suspicious and 10 [12%] atypical) diagnoses for lymphoma. Of the 68 primary lymphomas analyzed with FCM, 50 [74%] were true positives, and 28 were indeterminate (11 [16%] suspicious and 7 [10%] atypical). There were no false negatives. Diagnostic accuracy varied among lymphoma subtypes. Subclassification of the positive cases were initially conclusive in only 55/93 cases (59%). However, a retrospective review of the morphologic together with FCM data in 15 of the 23 unclassified cases improved the overall subclassification of positive cases to 77%. Subclassification was best in small lymphocytic lymphoma/chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, Burkitt's lymphoma, mantle cell lymphoma, and plasmacytoma (all 100%). Subclassification was poor in marginal-zone lymphoma (33%), and initially as well in diffuse large B-cell lymphoma (62%), but it improved on review (95%), as did subclassification of follicular lymphoma (77 to 100% on review). Hodgkin's disease was recognized as malignant in only 44% of the cases (7/16) and was classified as such based on morphology alone. This review of our early efforts to diagnose and subclassify lymphoma with FNAB and FCM indicates that although a diagnosis and proper subclassification of lymphoma can be made with certainty in the majority of cases, recurrent or primary, it requires close coordination of cytomorphology and immunophenotyping data, which often comes with close cooperation of cytopathologists and hematopathologists. A mere cytological diagnosis of positive for lymphoma is no longer acceptable if FNAB is to become an independent diagnostic tool for lymphoma.