Influence of CD27- CD28- T-Cells on the Therapeutic Outcome in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma after CART-Infusion

Background: Therapies involving adoptive transfer of chimeric antigen receptor-modified T-cells (CARTs) targeting CD19-expressing B-cells have shown remarkable efficacy in patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). We hypothesized, that a higher fraction of more differentiated, senescent and exhausted T-cells affects negatively ex vivo T-cell expansion in the manufacturing phase of CARTs and the in vivo function of CARTs after infusion. Of note, naïve CD4+ T-cells were shown to uniformly express the co-stimulatory receptors CD27 and CD28, while repeated cycles of activation led to their progressive loss (van Leewen et al, J. Immunol, 2004), accompanied by telomere erosion and replicative senescence (van Baarle et al., Immunol. Lett. 2005; Effros RB et al., Dev Comp Immunol 1997). CD28 expression on T-cells within the tumor environment was shown to be a decisive factor for the efficacy of anti-PD-1 therapy (Kamphorst RO et al, Science 2017). We have therefore analyzed the CD27 and CD28 expression status of CD3+ T-cells from the peripheral blood and apheresis products of adult r/r DLBCL patients at the day of leukapheresis. Methods: Peripheral blood and apheresis samples of 22 consecutive r/r DLBCL patients scheduled for CART therapy were analyzed by flow cytometry to assess their CD27 and CD28 expression status on CD3+ T-cells. Samples were stained with fluorochrome conjugated antibodies (anti-CD3 PerCP, anti-CD27 FITC, CD28 PE, anti-CD4 FITC, BioLegend) and analyzed using a FACScalibur flow cytometer supported by CELLQUEST software (Becton Dickinson, BD, Palo Alto, CA). Results: To rule out an apheresis-related bias within cell populations we analyzed peripheral blood and apheresis samples for each patient. No differences in the distribution of CD27-, CD28-, CD27-/CD28- or CD27+/CD28+ T-cells between peripheral blood and apheresis product were detected. Mean CD3+ cell count in blood samples before apheresis was 624±399/µl (range, 75-1853cells/µL) with only about 25% of the patients presenting with CD3+ cell counts within the normal range (690-3320/µL) and 70% of the patients showed an inverse CD4/CD8 ratio (<1.0). We observed a considerable heterogeneity within the T-memory cell compartment. In all samples high percentages of CD27- (39.7±18.1%), CD28- (40.2±19.0%) and CD27-/CD28- (30.7±19.8%) T-cells were seen when compared to healthy controls (CD27-: 15.2±9.9%; CD28-: 18.4±8.9%; CD27-/CD28-: 9.9±8.7%; p<0.05). Patients receiving CARTs were embedded within three different CART-trials (NCT02445248, NCT03630159, NCT03484702). A significantly lower frequency of CD27-/CD28-T-cells (20.8±18.8 vs 42.4±13.7%; p=0.045 Mann Whitney U) was found in responders (n=8) compared to non-responders (n=5; Figure 1a). We also noticed a higher frequency of CD27+/CD28+ T-cells (57.5±22.7% vs 44.3±11.7%; Figure 1b) and a trend towards a normal (>1.0) CD4/CD8 ratio (Figure 1c) in responding patients. Furthermore, we did not observe significant differences in CD27-and CD28- expression in samples derived from patients who died prior to receiving CART therapy (n=6) when compared to patients responding or progressing after CART therapy. Three patients have not been infused yet. Conclusion: We demonstrate in this small patient cohort that individuals with a lower percentage of more differentiated, senescent or exhausted T-cells are more likely to respond to CART therapy. Our observation underscores the importance of T-cells with normal replicative capacity in the apheresis material for consecutive CART production to achive therapeutic success. Further analysis is needed to determine the effect of cytotoxic pretreatment on the fraction of immunosenescent/exhausted T-cells. However, to confirm our findings additional investigations including the T-cell status of manufactured cells are warranted. Disclosures Worel: Sanofi Genzyme, Malinckrodt Therakos: Speakers Bureau; Sanofi Genzyme, Malinckrodt Therakos: Research Funding; Jazz, Sanofi, Celgene, Novartis, Malinckrodt Therakos: Honoraria. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria. Hopfinger:Celgene, Gilead, GlaxoSmithKline, Janssen, Novartis, Roche, Takeda,: Honoraria; Gilead: Research Funding.

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Somatic PRAME Deletions Are Associated with Decreased Immunogenicity, Apoptosis Resistance and Poor Outcomes in Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-113516 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 667-667

Author(s):

Katsuyoshi Takata ◽

Daisuke Ennishi ◽

Ali Bashashati ◽

Saeed Saberi ◽

Elena Viganò ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Wild Type ◽

Memory T Cell ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background: The current standard of care in diffuse large B-cell lymphoma (DLBCL) consists of chemotherapy and therapeutic monoclonal antibodies that have significantly improved patient outcomes over the past 15 years. However, a large proportion of patients suffer from refractory or relapsed disease. Therefore, the development of new therapeutic strategies for this subgroup of patients, who are threatened by a high chance of disease-related death, represents an important unmet clinical need. Methods: We enrolled into our study 347 de novo DLBCL patients uniformly treated with R-CHOP from the BC Cancer population-based cohort between September 2000 and January 2012. RNAseq and high-resolution copy number analysis were performed and correlated with clinical outcome data and tumor microenvironment composition. We also performed functional studies to investigate PRAME-mediated memory T-cell responses and gene expression changes. Results: We discovered novel, highly focal deletions of 22q11.22, including the PRAME gene in 13% (44/338) of the cases. The deletions cluster in a narrow chromosomal region that includes a very small number of genes (VpreB1, ZNF280A/B, PRAME, GGTLC2, miR-650). Of clinical importance, 22q11.22 deletions were found significantly more frequently in germinal centre B-cell-like (GCB) type DLBCL (17% (31/180) vs. activated B-cell-like (ABC) type: 8% (8/98), P < 0.01), and were also significantly associated with worse outcome, which was specifically observed in GCB-DLBCL (5-year disease specific survival, non-PRAME-deleted: 84.5% vs. PRAME-deleted: 67.2%, P = 0.026). Homozygous deletions were more strongly associated with poor outcome than heterozygous deletions. Interestingly, 90% of PRAME-deleted cases were Ig-lambda restricted (P < 0.001). PRAME is a prominent member of the cancer testis antigen (CTA) family of proteins that are expressed in various types of cancers, but not in normal tissues, including normal mature B-cells, apart from male germinal cells. Due to the cancer-specific expression of CTAs, these molecules are considered promising targets for cancer immunotherapy using cytotoxic T-cells and tumor vaccination approaches. To determine the association with tumor microenvironment composition, we analyzed CD4/CD8 flow cytometry data from DLBCL patient samples. The numbers of CD4 and CD8-positive T cells were significantly lower in PRAME-deleted cases compared to wild type (CD4: P < 0.001, CD8: P = 0.013). Notably, RNAseq analysis revealed that the HLA-A*0201 genotype was seen significantly more often in PRAME deleted cases (PRAME wt: 2.5% vs. PRAME deleted: 10.8%, P = 0.005). In order to functionally characterize its interaction with the immune microenvironment, we utilized enzyme-linked immunoSpot (ELISPOT) assays to investigate memory T-cell reactions of patient-derived T cells to PRAME antigens using patient-derived peripheral blood mononuclear cells (PBMC) and measured IFN-g production (7 control healthy donors, 4 PRAME-deleted and 4-wild type patients). While T cells from PRAME-replete patients had no reaction to PRAME antigens, PRAME-deleted patient-derived T-cells had significant reactions to 4 independent PRAME peptides. These data suggest that PRAME-deleted tumor cells can escape from cytotoxic T-cell attack to gain growth advantage. Next, we performed PRAME knock-out (KO) experiments using CRISPR/Cas9 genome editing to clarify the cell autonomous effects of PRAME deletions. Using 2 different cell lines (Karpas422 and SUDHL-4), we found TNFSF10 (TRAIL) expression was significantly down-regulated in homozygous PRAME-KO cell lines compared to wild type. The soluble form of TRAIL (sTRAIL) was also reduced, as measured with enzyme-linked immunosorbent assays. These results suggest that PRAME downregulated cells may contribute to cell survival via TRAIL and sTRAIL reduction. Conclusion: We identified recurrent PRAME deletions and characterized their clinical and functional role in DLBCL. Our findings contribute to the understanding of cell-autonomous and extrinsic roles of PRAME deletions in lymphomagenesis and may lead to the discovery of new therapeutic avenues to simultaneously treat the tumor and the host. Disclosures Gascoyne: NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Janssen: Research Funding; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Celgene: Consultancy, Honoraria. Steidl:Tioma: Research Funding; Seattle Genetics: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Consultancy; Nanostring: Patents & Royalties: patent holding.

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Use of immune repertoire sequencing to resolve discordant microscopic and immunochemical findings in a case of T cell-rich large B cell lymphoma in a young dog

BMC Veterinary Research ◽

10.1186/s12917-021-02783-3 ◽

2021 ◽

Vol 17 (1) ◽

Author(s):

Gary Kwok Cheong Lee ◽

Dorothee Bienzle ◽

Stefan Matthias Keller ◽

Mei-Hua Hwang ◽

Nikos Darzentas ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Immune Repertoire ◽

Large B Cell Lymphoma ◽

Repertoire Sequencing ◽

Reactive Lymphocytes ◽

Large B Cell

Abstract Background Lymphocytic neoplasms with frequent reactive lymphocytes are uncommonly reported in dogs, and can pose a diagnostic challenge. Different diagnostic modalities such as cytology, flow cytometry, histopathology, immunohistochemistry, and clonality testing, are sometimes required for a diagnosis. This report illustrates the value of using a multi-modal diagnostic approach to decipher a complex lymphocytic tumor, and introduces immune repertoire sequencing as a diagnostic adjunct. Case presentation A 10-month-old Great Dane was referred for marked ascites. Cytologic analysis of abdominal fluid and hepatic aspirates revealed a mixed lymphocyte population including numerous large lymphocytes, yielding a diagnosis of lymphoma. Flow cytometrically, abdominal fluid lymphocytes were highly positive for CD4, CD5, CD18, CD45, and MHC II, consistent with T cell lymphoma. Due to a rapidly deteriorating clinical condition, the dog was euthanized. Post mortem histologic evaluation showed effacement of the liver by aggregates of B cells surrounded by T cells, suggestive of hepatic T cell-rich large B cell lymphoma. Immune repertoire sequencing confirmed the presence of clonal B cells in the liver but not the abdominal fluid, whereas reactive T cells with shared, polyclonal immune repertoires were found in both locations. Conclusions T cell-rich large B cell lymphoma is a rare neoplasm in dogs that may be challenging to diagnose and classify due to mixed lymphocyte populations. In this case, the results of histopathology, immunohistochemistry and immune repertoire sequencing were most consistent with a hepatic B cell neoplasm and reactive T cells exfoliating into the abdominal fluid. Immune repertoire sequencing was helpful in delineating neoplastic from reactive lymphocytes and characterizing repertoire overlap in both compartments. The potential pitfalls of equating atypical cytomorphology and monotypic marker expression in neoplasia are highlighted.

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Clonal expanded TRA and TRB subfamily T cells in peripheral blood from patients with diffuse large B-cell lymphoma

Hematology ◽

10.1179/102453310x12583347009856 ◽

2010 ◽

Vol 15 (2) ◽

pp. 81-87 ◽

Cited By ~ 9

Author(s):

Huo Tan ◽

Jingmei Ye ◽

Xiaodan Luo ◽

Shaohua Chen ◽

Qingsong Yin ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Peripheral Blood ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Nodular Lymphocyte Predominant Hodgkin Lymphoma: A Rare Case with Fan Pattern E

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqaa161.234 ◽

2020 ◽

Vol 154 (Supplement_1) ◽

pp. S107-S107

Author(s):

E Ozluk ◽

E Wei

Keyword(s):

T Cells ◽

Lymph Node ◽

T Cell ◽

B Cell ◽

Hodgkin Lymphoma ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Atypical Cells ◽

Large B Cell

Abstract Introduction/Objective Growth patterns of nodular lymphocyte predominant Hogdkin lymphoma (NLPHL) has been further described by Fan et all. Pattern E is T cell/histiocyte rich large B-cell lymphoma-like and is quite rare. The treatment usually may follow large B cell lymphoma protocol instead of Hodgkin lymphoma regimen. Methods Here we report a patient with NLPHL pattern E. Patient was a 25 years-old African American man who initially presented with generalized lymphadenopathy. Results Biopsy of the axillary lymph node revealed effaced lymph node architecture by a malignant neoplasm in a diffuse and vaguely nodular pattern. In the background of a diffuse infiltrate, there were small to medium sized lymphocytes, numerous atypical large cells with irregular, basophilic nucleoli, and variable cytoplasm. The large cells focally sheeted out. Many histiocytes were also seen in the background. The large atypical cells were positive for CD20, BOB-1, OCT2, BCL-2 (focally), BCL-6, PAX5, and MUM-1, and IgD, whereas negative for BCL-1, CD10, CD15, CD30. CD2, CD3, CD4, CD5, CD7, CD8 highlighted numerous T cells with mild cytological atypia, forming rosettes around the large atypical cells. T cells were negative for ALK-1, CD1a, TdT with increased Ki-67 proliferation index around 35%. Although the surrounding T cells appear atypical in morphology, flow cytometric analysis showed predominantly reactive T-cells with no loss of T-cell associated antigens. PCR analysis showed a producible peak in a single IgH reaction. However, the fragment size of the peak observed did not meet the criteria. T-cell gene rearrangement by TCR gamma and TCR beta PCR was negative for monoclonal T-cells. BCL-1, BCL-2, and BCL-6 FISH panel were negative for gene rearrangements. Based on these findings the diagnosis was made at stage IV. Patient started treatment with R-CHOP therapy with subsequent relapse. Patient has been placed on RICE chemotherapy with partial response. Conclusion NLPHL Pattern E type should be differentiated from classical Hodgkin lymphoma, diffuse large B-cell lymphoma and peripheral T cell lymphoma because the treatment greatly differs from those with higher stage and tendency for recurrence. It is the pathologist role to lead the clinician and render a correct histopathologic diagnosis.

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Peripheral Blood Lymphocytic Profile in Patients with Diffuse Large B Cell Lymphoma and Follicular Lymphoma.

Blood ◽

10.1182/blood.v106.11.4656.4656 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4656-4656

Author(s):

Fernando Cavallin ◽

Giovanni Vicario ◽

Paolo Manente ◽

Rosa Di Gaetano ◽

Giuseppe Tagariello

Keyword(s):

Flow Cytometry ◽

T Cells ◽

B Cell ◽

Peripheral Blood ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Peripheral Blood Lymphocytes ◽

Over Expression ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Diffuse Large B Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) are the most common adult low-grade non Hodgkin’s lymphomas. The influence of these diseases in peripheral blood lymphocytes is not well defined. Indeed the lymphocytic arrangement can be altered on account of the leukaemic form (although it slightly ever occurs); on the other hand the cause of occasional anomalies can be the involvement of the immune system against neoplasm. In order to contribute to the knowledge of these conditions we have analysed, at diagnosis, the lymphocytic immunophenotype in peripheral blood of 61 subjects: 27 were affected by DLBCL, average age 68, and 34 by FL, average age 61 years. Therefore we quantified the number of lymphocytes and evaluated essential markers, using flow cytometry, to define T, B, NK subsets by: CD3, CD4, CD8, CD19, SIgk, Sigl, CD56, and expression of CD11a molecule on T CD8. The absolute peripheral blood lymphocytes count presented a reduction in 51% and in 32% of the cases with an increase in 4% and in 3% of the subjects respectively considering DLBCL and FL. On the contrary T cells (CD3) had similar decrease, 33% and 32%, and different augmentation 15% and 3%. T cells ratio CD4/CD8 was under normal in 23% and in 12% of the patients but over normal in 12% and 29% always in DLBCL and FL. B cells (CD19) were reduced in 35% and in 12% of the subjects but increased in 8% and in 14%, whereas clonal restriction was present in 8% and in 20% of the components of the two groups. Natural Killer lymphocytes (CD56) were under normal in 12% and in 6% of bthe cases but over in 40% and 20%. Finally CD11a was over-expressed in 87% and in 68% of the patients of the respective pathologies. After selecting patients aged over 60 years, following four parameters that showed a significant variability was obtained: 1) lymphopenia in 50% of the cases in both groups; 2) similar results 11% and 15% about clonal restriction; 3) increase of the NK population 42% and 30% in DLBCL and FL; 4) very high over-expression of CD11a on T CD8 of 90% and 80%. Therefore DLBCL and FL are lymphoproliferative diseases where there is an important subtraction of lymphocytes, particularly in elderly people, from peripheral blood (perhaps because of accumulation in lymphnodes). These lesions present clonal restriction of B cells only in few cases (confirming the low known leukaemic form) while Natural Killer population are well represented especially in DLBCL. The over-expression of CD11a is the most altered parameter and seems almost a typical marker of these diseases above all in over 60 years subjects. Consequently if rarely happens that a leukaemic form of DLBCL and FL are found by flow cytometry however immunological defined alterations are very frequent in most of the cases of old patients.

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Fatal late-onset CAR T-cell–mediated encephalitis after axicabtagene-ciloleucel in a patient with large B-cell lymphoma

Blood Advances ◽

10.1182/bloodadvances.2021004889 ◽

2021 ◽

Vol 5 (19) ◽

pp. 3789-3793

Author(s):

Susanne Jung ◽

Jochen Greiner ◽

Stephanie von Harsdorf ◽

Pavle Popovic ◽

Roland Moll ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Car T Cells ◽

Car T Cell ◽

Large B Cell Lymphoma ◽

Car T ◽

Large B Cell

Abstract Treatment with CD19-directed (CAR) T cells has evolved as a standard of care for multiply relapsed or refractory large B-cell lymphoma (r/r LBCL). A common side effect of this treatment is the immune effector cell–associated neurotoxicity syndrome (ICANS). Severe ICANS can occur in up to 30% to 40% of patients treated with axicabtagene-ciloleucel (axi-cel), usually within the first 4 weeks after administration of the dose and usually responding well to steroids. We describe a case of progressive central neurotoxicity occurring 9 months after axi-cel infusion in a patient with r/r LBCL who had undergone a prior allogeneic hematopoietic cell transplant. Despite extensive systemic and intrathecal immunosuppression, neurological deterioration was inexorable and eventually fatal within 5 months. High CAR T-cell DNA copy numbers and elevated levels of interleukin-1 (IL-1) and IL-6 were found in the cerebral spinal fluid as clinical symptoms emerged, and CAR T-cell brain infiltration was observed on autopsy, suggesting that CAR T cells played a major pathogenetic role. This case of unexpected, devastating, late neurotoxicity warrants intensified investigation of neurological off-target effects of CD19-directed CAR T cells and highlights the need for continuous monitoring for late toxicities in this vulnerable patient population.

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Outcomes of Large B-Cell Lymphoma Patients By Post CAR-T Salvage Regimen at a Single Institution

Blood ◽

10.1182/blood-2021-148751 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3851-3851

Author(s):

Audrey M. Sigmund ◽

Nathan Denlinger ◽

Amneet Bajwa ◽

Patrick Elder ◽

David A. Bond ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Regimen ◽

Large B Cell Lymphoma ◽

Car T ◽

Large B Cell

Abstract Introduction: Outcomes of patients with large B-cell lymphoma that relapse after frontline anthracycline based chemotherapy are typically poor, with a 3-year event-free survival of approximately 30% (Gisselbrecht JCO 2010). Chimeric antigen receptor T-cell (CAR-T) therapy represents a breakthrough therapy for these patients, with an overall response rate (ORR) of 83% and a complete response (CR) rate of 58% for axicabtagene ciloleucel (axi-cel) seen in the ZUMA-1 trial, with similar rates for tisagenlecleucel in the JULIET trial (Locke Lancet Oncol 2018; Schuster NEJM 2018). Unfortunately, the majority of patients treated with CAR-T therapy experience disease progression. There is limited data evaluating the best salvage regimen for these patients. Thus, we sought to assess outcomes in large B-cell lymphoma patients with progressive disease post CAR-T cell therapy with the goal of identifying those therapies with optimal outcomes. Methods: A retrospective study was performed on all patients with large B-cell lymphoma undergoing leukapheresis for CAR-T therapy (tisagenlecleucel or axi-cel) at the Ohio State University from December 2017 to January 2021. Patients who died prior to CAR-T infusion were excluded from analysis. Demographics and disease characteristics as well as best response to CAR-T and date of relapse or progression following therapy were collected. First salvage therapy at relapse or progression and response to therapy were also collected, with choice of therapy driven by the treating physician. Patients were divided by salvage regimen into five groups for analysis: checkpoint inhibitor based, lenalidomide based, Bruton Tyrosine Kinase inhibitor (BTKi), chemoimmunotherapy, and other (including small molecular inhibitor, radiation, allogeneic stem cell transplant, antibody drug conjugates, and bispecific antibodies). The primary endpoint was overall survival (OS), which was calculated using Kaplan Meier Curves. Rates of CR and ORR were also assessed. Results: A total of 144 patients underwent leukapheresis for CAR-T cell therapy during the time period; of these patients, 13 died prior to undergoing CAR-T cell infusion and were excluded from analysis. The primary cohort included 131 patients. Median age at the time of T-cell collection was 62 years old (range 23-85) and 61% were male. The majority (50%) had germinal center (GCB) subtype, with 42% non-GCB and subtype unavailable for 8%. A small number (3%) had primary mediastinal B-cell lymphoma. The majority had high-risk disease, with 45% having primary refractory disease, 14.5% double or triple hit, and 81% Ann Arbor stage III or IV at diagnosis. Median prior lines of therapy was 3 (range 0-10). Sixty-six patients received axi-cel and 65 patients received tisagenlecleucel. Forty percent of patients attained a CR, 18% partial response (PR), 3% stable disease (SD), 33% progressive disease (PD), and 6% of patients died prior to disease assessment. For those 76 patients that received a CR or PR to therapy, 43% relapsed post CAR-T and 57% remained in CR at last follow-up. Of those patients who relapsed or progressed post CAR-T, 69% (54/78) patients received additional therapy. The most common therapies utilized were lenalidomide based (35%), BTKi (22%), chemoimmunotherapy (13%), and checkpoint inhibitor based (15%). Other therapies represented 15% of cases and included small molecular inhibitor, radiation, allogeneic stem cell transplant, antibody drug conjugates, and bispecific antibodies (Table 1). Overall response rates and median OS for the groups were 50% and 2.25 years for BTKi, 13% and 0.96 years for checkpoint inhibitor based, 71% and not reached (NR) for chemoimmunotherapy, 47% and 2.4 years for lenalidomide based, and 75% and NR for other (Table 1; Figure 1). Median OS for those patients who did not receive any salvage therapy was 0.19 years. Conclusion: Consistent with prior studies, median OS following relapse post CAR-T therapy was poor, with median OS 0.19 years for patients who did not receive therapy and ranging from 0.96 years to NR for those that did. Rates of CR were highest in patients treated with BTKis. In our series, ORR rate to checkpoint inhibitors was relatively low in contrast to other recently published retrospective reports. Future prospective studies are needed to further assess the optimal therapy for patients who relapse post CAR-T therapy. Figure 1 Figure 1. Disclosures Bond: Kite/Gilead: Honoraria. Brammer: Seattle Genetics: Speakers Bureau; Kymera Therapeutics: Consultancy; Celgene: Research Funding. de Lima: Miltenyi Biotec: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Jaglowski: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy. Kittai: Bristol-Meyers Squibb: Consultancy; Janssen: Consultancy; Abbvie: Consultancy.

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A Rare Case of T-Cell Histiocyte Rich Large B-Cell Lymphoma of the Thyroid in a Patient With Hashimotos

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1796 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A879-A880

Author(s):

Abir Zainal ◽

Jhansi Maradana ◽

Mira Torres

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Thyroid Gland ◽

Lymph Nodes ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Introduction: T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare form of large B-cell lymphoma, which usually involves the lymph nodes exclusively. We describe a patient with Hashimoto’s thyroiditis who was discovered to have THRLBCL arising from the thyroid. Clinical Case: A 78-year-old female with a history of Hashimoto’s thyroiditis noted increase in the size of her left thyroid lobe for two months despite normal TSH on Levothyroxine, prompting an ultrasound which revealed several enlarged left sided cervical lymph nodes and an enlarged left thyroid gland. Cytology from an FNA of a left level 3 lymph node showed atypical lymphoid infiltrate featuring scattered large atypical cells in a background of small lymphocytes. Immunohistochemical testing was PAX5+, CD30- and CD15-. Cytology from an FNA of left thyroid revealed identical changes and immunohistochemistry demonstrated PAX5+ and CD20+. Concurrent flow cytometric studies demonstrated increased CD4 to CD8 ratio among T cells. Excisional biopsy of a left cervical lymph node confirmed a diagnosis of THRLBCL. PET/CT exhibited lymphadenopathy above her diaphragm and splenic involvement. Her bone marrow biopsy was negative for involvement. She was deemed Stage III with international prognostic index (IPI) of 2 corresponding with low-intermediate risk. She was commenced on chemotherapy R-CHOP with plan to complete 6 cycles. Discussion: THRLBCL is characterized by scattered atypical B lymphocytes on a background of T lymphocytes and histiocytes. Usually, T-cells are predominantly CD8+, in contrast to our patient. Some studies identified cases of predominant CD4+ and PD1+ T cells. Cytology revealed scattered small B-cells and large B-cells, a feature that is not typically seen in THRLBCL. A diagnosis of diffuse transformation of nodular lymphocyte predominant Hodgkin lymphoma was considered but the diffuse proliferation outside of CD21+ and involvement of the thyroid is not compatible with such diagnosis. Similarly, a diagnosis of follicular helper T-cell lymphoma with admixed large B-cells was considered but while PD1+ CD4+ T cells are present, there was no aberrant antigen expression by flow cytometry or T cell clonality. THRLBCL mainly involves lymph nodes and presents at advanced Ann Arbor stages with high IPI. Malignant lymphomas of the thyroid gland are exceedingly rare, accounting for 2% of thyroid cancers, out of which the literature reveals a single case report of THRLBCL arising from the thyroid. THRLBCL represents an aggressive form of lymphoma and is treated according to stage-matched DLBCL, although the effects of Rituximab in this population is variable. Conclusion: Hashimoto’s is considered a risk for thyroid lymphoma usually diffuse large B-cell lymphoma and MALT lymphoma. We present a rare case of THRLBCL occurring in the setting of Hashimoto’s with acute thyroid gland enlargement.

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