Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy in T-cell/histiocyte-rich large B-cell lymphoma.
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ABSTRACT:
SUBMITTER: Trujillo JA
PROVIDER: S-EPMC8212512 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
Publications
Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy in T-cell/histiocyte-rich large B-cell lymphoma.
Trujillo Jonathan A JA Godfrey James J Hu Yifei Y Huang Jun J Smith Sonali M SM Frigault Matthew J MJ DeFilipp Zachariah Z Appelbaum Daniel D Pu Yonglin Y Feinberg Nicholas N Althaus Thomas T Bishop Michael R MR Riedell Peter A PA Kline Justin J
Blood 20210601 24
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Project description:Potential CD19 antigen loss following CD19-directed therapy has raised concerns over sequential use of these therapies. Tafasitamab, a CD19-targeting immunotherapy, combined with lenalidomide, is approved for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) treatment in adults ineligible for autologous stem cell transplantation. This retrospective analysis examined characteristics and outcomes of adults with R/R DLBCL who received tafasitamab preceding CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy in a real-world setting. Nine patients received tafasitamab and lenalidomide immediately preceding CAR-T. Median (first quartile [Q1]-third quartile [Q3]) follow-up time since tafasitamab initiation was 26.1 (18.0-28.0) and after CAR-T was 9.3 (1.9-16.7) months. Of the 9 patients, 4 had complete response, 4 had partial response, and 1 had stable disease following tafasitamab; all discontinued tafasitamab due to disease progression. Median (Q1-Q3) tafasitamab therapy duration was 11.0 (8.1-14.1) months. Three patients had CD19 testing following tafasitamab discontinuation, and all tests were positive. Median (Q1-Q3) time from tafasitamab discontinuation to CD19 testing was 7 (6-9) days. Among the 9 patients, median (Q1-Q3) time from tafasitamab discontinuation to CAR-T administration was 3.2 (2.3-3.6) months. Four patients had complete response, 3 had partial response, and 1 had progressive disease as best response to CAR-T; 1 patient had data unavailable. This small real-world analysis demonstrated disease response to CAR-T therapy and detectable CD19 expression following tafasitamab treatment, adding to literature investigating treatment outcomes associated with sequential use of anti-CD19 therapies in patients with R/R DLBCL.
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Project description:AbstractAlthough broadly used, consolidative autologous hematopoietic stem cell transplantation (auto-HCT) for relapsed/refractory (R/R) T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) has never been specifically investigated. Here, we have analyzed outcomes of auto-HCT for THRLBCL compared with diffuse large cell B-cell lymphoma not otherwise specified (DLBCL). Eligible for this retrospective registry study were adult patients with R/R THRLBCL and DLBCL, respectively, who underwent a first auto-HCT in a salvage-sensitive disease status as assessed by positron emission tomography-computed tomography between 2016 and 2021 and were registered with the European Society for Blood and Marrow Transplantation database. The primary end point was progression-free survival (PFS) 2 years after transplantation. A total of 201 patients with THRLBCL and 5543 with DLBCL were included. There were no significant differences in terms of disease status at HCT, pretreatment lines, and interval from diagnosis to transplant between the cohorts, but patients with THRLBCL were significantly younger, contained a higher proportion of men, and had a better performance status. Compared with DLBCL, THRLBCL was associated with significantly better 2-year PFS (78% vs 59%; P < .001) and overall survival (OS, 81% vs 74%; P = .02) because of a significantly lower 2-year relapse incidence (16% vs 35%; P < .001). On multivariate analysis, favorable relapse risk (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.31-0.7) and PFS (HR, 0.58; 95% CI, 0.41-0.82) of patients with THRLBCL remained significant, whereas OS benefits (HR, 0.78; 95% CI, 0.54-1.12) did not. These results were validated in a propensity score-matched analysis. These data prove auto-HCT as an effective treatment option for salvage-sensitive R/R THRLBCL.
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Project description:In contrast to the commonly indolent clinical behavior of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), T cell/histiocyte rich large B cell lymphoma (THRLBCL) is frequently diagnosed in advanced clinical stages and has a poor prognosis. Besides the different clinical presentations of these lymphoma entities, there are variants of NLPHL with considerable histopathologic overlap compared to THRLBCL. Especially THRLBCL-like NLPHL, a diffuse form of NLPHL, often presents a histopathologic pattern similar to THRLBCL, suggesting a close relationship between both lymphoma entities. To corroborate this hypothesis, we performed gene expression profiling of microdissected tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. In unsupervised analyses, the lymphomas did not cluster according to their entity. Moreover, even in supervised analyses, very few consistently differentially expressed transcripts were found, and for these genes the extent of differential expression was only moderate. Hence, there are no clear and consistent differences in the gene expression of the tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. Based on the gene expression studies, we identified BAT3/BAG6, HIGD1A, and FAT10/UBD as immunohistochemical markers expressed in the tumor cells of all three lymphomas. Characterization of the tumor microenvironment for infiltrating T cells and histiocytes revealed significant differences in the cellular composition between typical NLPHL and THRLBCL cases. However, THRLBCL-like NLPHL presented a histopathologic pattern more related to THRLBCL than NLPHL. In conclusion, NLPHL and THRLBCL may represent a spectrum of the same disease. The different clinical behavior of these lymphomas may be strongly influenced by differences in the lymphoma microenvironment, possibly related to the immune status of the patient at the timepoint of diagnosis.
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