Lack of Survival Improvement in Patients with Large Cell Lymphomas of T-Cell Phenotype: A SEER Analysis Comparing Outcomes According to Phenotype and Year of Diagnosis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3577-3577
Author(s):  
Daniel Morgensztern ◽  
Gail Walker ◽  
Leonidas Koniaris ◽  
Izidore S. Lossos
Keyword(s):  
T Cell ◽  
B Cell ◽  
Poor Prognosis ◽  
Stage Iv ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Good Prognosis ◽  
Cell Phenotype ◽  
Survival Difference ◽  
Over Time

Abstract Background: The majority of studies suggest that among patients with aggressive non-Hodgkin lymphomas (NHL), T-cell phenotype (TCP) confers a poor prognosis. The worse outcomes in TCP may have become more accentuated since the introduction of rituximab, which has been associated with improved survival in patients with diffuse large B-cell lymphoma (DLBCL). The purpose of our study was to evaluate changes in NHL-survival (NHLS) according to immunophenotype and diagnostic era in a large sample of tumor registry cases. Methods: We analyzed SEER-reported cases aged 19 or older, diagnosed with NHL during the period from 1992 to 2003, and with available information on covariates including gender, race, site of disease, and stage at presentation. Lymphomas with ICD-0-3 codes 9675, 9680, or 684 and B-cell immunophenotype were classified as DLBCL, while TCP cases were identified by codes 9675, 9680, 9684, or 9702 and T-cell immunophenotype. NHLS was analyzed separately for cases diagnosed in 1992–1997 (era 1), and 1998–2003 (era 2), using SAS v9.1. We report 5-year Kaplan-Meier estimates and log rank comparisons, by cell type and era, adjusted for age and SEER summary stage. Since SEER data does not include IPI, we also analyzed two subgroups: patients under age 60 with Ann Arbor stage I/II disease (very good prognosis), and patients with age 60 and older with stage IV (poor prognosis). Results: Based on 7,359 study cases (6,526 DLBCL; 833 TCP) from era 1 and 18,099 (16,858 DLBCL; 1,241 TCP) from era 2, NHLS was significantly better in patients with B-cell v T-cell phenotype (p<0.001 both eras). Five-year rates were 54.4% v 42.9% in era 1, and 61.3% v 42.2% in era 2. Improvement for DLBCL in era 2 compared with era 1 was also significant (p<0.001), while there was no change for TCP (p=0.708). For the subgroup with very good prognosis, outcomes were comparable for DLBCL and TCP in era 1 but significantly different in era 2 (p=0.531 and p<0.001). The outcome for DLBCL patients with good prognosis improved over time (p<0.001) whereas similar benefit was not seen in TCP patients (p=0.273). Five-year NHLS rates were 75.2% v 73.8% in era 1, and 84.7% v 66.6% in era 2. In the poor prognosis subgroup, TCP was associated with worse outcome in both eras (p=0.011 and p=0.001). For these patient population, improvement in NHLS over time was not statistically significant for either DLBCL (p=0.076) or TCP (p=0.858). Five-year rates for DLBCL versus TCP were 30.6% v 22.2% in era 1, and 35.5% v 25.3% in era 2. Conclusions: The survival difference between DLBCL and TCP increased significantly after 1997 and is most likely attributable to widespread use of rituximab for B-cell lymphomas during the period 1998–2003. In DLBCL, the improved outcome was seen mainly in patients with good prognosis. In contrast, there were no significant advances in the treatment of T-cell lymphomas. Novel therapies are urgently needed in patients with TCP.

scholarly journals T-cell-rich B-cell lymphoma

Blood ◽  
1993 ◽  
Vol 82 (5) ◽  
pp. 1586-1589 ◽  
Author(s):  
J Rodriguez ◽  
WC Pugh ◽  
F Cabanillas
Keyword(s):  
T Cell ◽  
B Cell ◽  
Total Population ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Response To Therapy ◽  
Serum Lactate Dehydrogenase ◽  
Cell Phenotype ◽  
Large Cell Lymphoma

We analyzed 23 cases of T-cell-rich B-cell lymphomas (BCL) to determine if the clinical features are characteristic of a discrete entity. Cases encoded as T-cell-rich BCL in the hematopathology archives of the University of Texas M.D. Anderson Cancer Center between 1988 and 1991 formed the basis of this study. At least 50% of the total population of cells were required to be of T-cell phenotype. Actually, all but one patient had more than 70% T cells in the total population. Sixty-five percent of all cases were referred with other diagnosis such as Hodgkin's mixed cellularity, peripheral T-cell lymphoma (PTCL), or diffuse mixed lymphoma, and had received therapy accordingly. With the exception of splenomegaly, which occurred in 35% of cases, the other clinical characteristics and the response to therapy did not indicate that this entity represents a distinct type of lymphoma. Ann Arbor stage I-II presentations were seen in 10 of 23 (43%) T-cell-rich BCLs. Serum lactate dehydrogenase (LDH) was elevated in eight of 19 patients. Age, sex, and beta 2-microglobulin were not significantly different from classical B-cell large cell lymphoma. The clinical presentation and clinical outcome of T-cell-rich BCL did not differ from that of common B-cell large cell lymphoma, except for the higher proportion of splenomegaly seen in patients with T-cell-rich BCL. The presence of the T-cell-rich infiltrate varied: it frequently was not seen at relapse or at other sites of disease at presentation. It was thus considered an unstable parameter. The major importance of identifying this entity is to distinguish it pathologically from other disorders such as Hodgkin's disease and PTCL, which would be treated in a different manner.

scholarly journals T-cell-rich B-cell lymphoma

Blood ◽  
1993 ◽  
Vol 82 (5) ◽  
pp. 1586-1589 ◽  
Author(s):  
J Rodriguez ◽  
WC Pugh ◽  
F Cabanillas
Keyword(s):  
T Cell ◽  
B Cell ◽  
Total Population ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Response To Therapy ◽  
Serum Lactate Dehydrogenase ◽  
Cell Phenotype ◽  
Large Cell Lymphoma

Abstract We analyzed 23 cases of T-cell-rich B-cell lymphomas (BCL) to determine if the clinical features are characteristic of a discrete entity. Cases encoded as T-cell-rich BCL in the hematopathology archives of the University of Texas M.D. Anderson Cancer Center between 1988 and 1991 formed the basis of this study. At least 50% of the total population of cells were required to be of T-cell phenotype. Actually, all but one patient had more than 70% T cells in the total population. Sixty-five percent of all cases were referred with other diagnosis such as Hodgkin's mixed cellularity, peripheral T-cell lymphoma (PTCL), or diffuse mixed lymphoma, and had received therapy accordingly. With the exception of splenomegaly, which occurred in 35% of cases, the other clinical characteristics and the response to therapy did not indicate that this entity represents a distinct type of lymphoma. Ann Arbor stage I-II presentations were seen in 10 of 23 (43%) T-cell-rich BCLs. Serum lactate dehydrogenase (LDH) was elevated in eight of 19 patients. Age, sex, and beta 2-microglobulin were not significantly different from classical B-cell large cell lymphoma. The clinical presentation and clinical outcome of T-cell-rich BCL did not differ from that of common B-cell large cell lymphoma, except for the higher proportion of splenomegaly seen in patients with T-cell-rich BCL. The presence of the T-cell-rich infiltrate varied: it frequently was not seen at relapse or at other sites of disease at presentation. It was thus considered an unstable parameter. The major importance of identifying this entity is to distinguish it pathologically from other disorders such as Hodgkin's disease and PTCL, which would be treated in a different manner.

scholarly journals Evaluation of the Revised European-American Lymphoma Classification Confirms the Clinical Relevance of Immunophenotype in 560 Cases of Aggressive Non-Hodgkin's Lymphoma

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4514-4520 ◽  
Author(s):  
A. Melnyk ◽  
A. Rodriguez ◽  
W.C. Pugh ◽  
F. Cabannillas
Keyword(s):  
Multivariate Analysis ◽  
T Cell ◽  
B Cell ◽  
Clinical Relevance ◽  
Poor Prognosis ◽  
Good Prognosis ◽  
Cell Phenotype ◽  
European American ◽  
Significant Prognostic Factor ◽  
Hodgkin's Lymphomas

Abstract The Revised European-American Lymphoma (REAL) classification has been criticized for its emphasis on the unproven clinical relevance of immunophenotype. A worse prognosis for peripheral T-cell non-Hodgkin's lymphomas (PTCLs) has been inconsistently reported in part because the definition of PTCL has been imprecise (eg, T-cell–rich B-cell non-Hodgkin's lymphomas [TCRBCLs] have been misdiagnosed as PTCLs in the past) and because its correlation with other known prognostic factors has not been studied by multivariate analysis. We analyzed six protocols from 1984 to 1995 with Working Formulation intermediate grade and immunoblastic lymphomas (exclusive of mantle cell) and selected only those cases in which immunophenotyping was performed and was conclusive. Of a total of 560 evaluable patients, 68 were PTCLs (12%) and the remaining 492 (88%) were B-cell non-Hodgkin's lymphomas, including 16 TCRBCLs (3% of total). The 5-year failure-free survival (FFS) for PTCLs and B-cell large-cell lymphomas (BCLCLs) is 38% and 55%, respectively (P < .0001) and the 5-year overall survival (OS) is 39% and 262%, respectively (P < .001). The M.D. Anderson prognostic tumor score (MDATS) and International Prognostic Index (IPI) for all patients was calculated. With MDATS of less than 3 (good prognosis), the 5-year FFS for PTCL and BCLCL is 56% and 69%, respectively (P = .01), and the 5-year OS is 64% and 77%, respectively (P = .06). With MDATS of greater than 2 (poor prognosis), 5-year FFS for PTCL and BCLCL is 26% and 38%, respectively (P = .03), and the 5-year OS is 24% and 41%, respectively (P = .02). With an IPI of less than 3 (good prognosis), the 5-year FFS for PTCL and BCLCL is 49% and 64%, respectively (P = .001), and the 5-year OS is 55% and 71%, respectively (P = .013). With an IPI greater than 2 (poor prognosis), the 5-year FFS for PTCL and BCLCL is 11% and 35%, respectively (P = .044), and the 5-year OS is 10% and 40%, respectively (P = .011). Multivariate analysis shows that MDATS, IPI, and T-cell phenotype are totally independent and are the most significant predictors of FFS and OS. The 68 PTCLs include 45 PTCLs unspecified, 10 Ki-1 anaplastic (ALCL), 8 angioimmunoblastic, and 5 angiocentric lymphomas. Angiocentrics were usually refractory (1 of 5 remissions only). ALCL rarely relapsed late. We conclude that the immunophenotypic basis of the REAL classification is clinically relevant and that, although other prognostic features also influence outcome, the T-cell phenotype still remains an independent and significant prognostic factor.

Primary T-Cell–Rich B-Cell Lymphoma Masquerading as a Meningioma

2000 ◽  
Vol 124 (11) ◽  
pp. 1700-1703
Author(s):  
Barbara H. Amaker ◽  
Nitya R. Ghatak ◽  
Sean A. Jebraili ◽  
Andrea Ferreira-Gonzalez ◽  
Michael J. Kornstein
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Molecular Techniques ◽  
First Case ◽  
Dural Lymphoma ◽  
Immunohistochemical Techniques

Abstract Primary dural lymphoma is rare, and few of the small number of cases reported to date have been classified using immunohistochemical techniques. To our knowledge, we report the first case of T-cell–rich B-cell lymphoma (diffuse mixed small cell and large cell) presenting as a solitary intracranial dural mass. Cytologic and frozen sections prepared during intraoperative consultation revealed a polymorphic population of lymphocytes suspicious for an inflammatory process. Permanent sections of the dura showed a diffusely infiltrating mass composed of mature lymphocytes peppered with large atypical lymphocytes. Immunohistochemical stains identified the small lymphocytes as T cells (CD3 and CD43) and the large atypical lymphocytes as B cells (CD20). Evidence of rearranged immunoglobulin heavy-chain genes demonstrated B-cell monoclonality. Differentiating between inflammatory and neoplastic lymphocytic masses of the dura obviously has important therapeutic and prognostic significance and may require immunohistochemical and molecular techniques.

Cutaneous lymphomas other than mycosis fungoides: follow-up study of 52 patients.

1991 ◽  
Vol 9 (11) ◽  
pp. 1994-2001 ◽  
Author(s):  
P Joly ◽  
F Charlotte ◽  
M Leibowitch ◽  
C Haioun ◽  
J Wechsler ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Mycosis Fungoides ◽  
Stage Iv ◽  
Disease Stage ◽  
Cell Phenotype ◽  
Low Grade ◽  
Cutaneous Lymphomas ◽  
Radiotherapy Alone

Cutaneous lymphomas other than mycosis fungoides (MF) represent a rare and heterogeneous group of lymphomas. Their clinical behavior remains largely unknown. In this study, the clinical and immunohistologic characteristics and follow-up data of 52 well-documented cases of cutaneous lymphomas other than MF, presenting with initial cutaneous lesions, were reviewed. Twenty-seven patients presented with skin disease alone (stage IE), and 25 patients had concurrent cutaneous and extracutaneous disease (stage IV). The tumors were grouped into high-grade lymphomas (HGLs; 21%), intermediate-grade lymphomas (IGLs; 58%), and low-grade lymphomas (LGLs; 21%). A B-cell phenotype was most often expressed by cutaneous lymphomas (73%), particularly by stage IE lymphomas (85%). Among 13 cases of T-cell lymphomas, loss of one of the pan-T-cell antigens was detected in all cases but one. The clinical course of cutaneous lymphoma was closely dependent on stage and histologic subtype but not on T-cell or B-cell phenotype. Of 20 patients with stage IV HGL or IGL, 13 were treated by polychemotherapy with curative potential. Their median survival was 37 months. Fourteen patients with stage IE HGL or IGL were treated by radiotherapy alone. Nine patients (69%) relapsed within 2 years posttreatment. Seven of them relapsed in the skin outside the initial site involved, suggesting that radiotherapy alone is not an adequate treatment for these patients. Preliminary results concerning seven other patients with stage IE IGL or HGL treated by an initial third-generation polychemotherapy regimen are presented.

Expression of X-Linked Inhibitor of Apoptosis Protein in Reactive Lymphoid Tissues, Non-Hodgkin’s Lymphomas, and Hodgkin’s Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4655-4655
Author(s):  
James A. Strauchen ◽  
David Burstein
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Hodgkin Disease ◽  
Large B Cell Lymphoma ◽  
Apoptosis Protein ◽  
Mantle Cell ◽  
Large B Cell

Abstract X-linked inhibitor of apoptosis protein (XIAP) is an important regulator of apoptosis which binds to and inhibits caspases-3, -7 and -9, blocking the caspase 9-mediated apoptosis pathway. This pathway is activated by p53 and DNA damage and may be an important determinant of responsiveness to chemotherapy. Apoptosis also plays a major role in the regulation of follicle center B-cell proliferation and BCL2-mediated inhibition of apoptosis is a key factor in B-cell lymphomagenesis. In this study we examined the expression of XIAP in 65 reactive and neoplastic lymphoid proliferations utilizing a monoclonal antibody to XIAP (#610763 BD Biosciences, San Jose, CA) and immunohistochemistry with avidin-biotin-complex immunoperoxidase technique on formalin-fixed, paraffin-embedded sections. In reactive lymph nodes and tonsils, expression of XIAP was limited to large noncleaved cells in follicle centers (5 of 6 cases). XIAP was absent in plasmacytoma (3 cases) and small lymphocytic lymphoma/chronic lymphocytic leukemia (1 case). XIAP was expressed in follicular lymphoma, predominantly in large noncleaved cells (6 of 9 cases) and in diffuse large B cell lymphoma (11 of 16 cases), including cases of T-cell/histiocyte-rich diffuse large B cell lymphoma (2 cases), primary mediastinal large B cell lymphoma (1 case), and posttransplantation diffuse large B cell lymphoma (1 case). XIAP was consistently expressed in Burkitt and Burkitt-like lymphoma (3 of 3 cases) and anaplastic large cell lymphoma (3 of 3 cases) and in one case of adult T cell leukemia/lymphoma. XIAP was variably expressed in marginal-zone B cell lymphoma, predominantly in large blasts (2 of 4 cases) and in mantle cell lymphoma (2 of 3 cases). XIAP was not detected in peripheral T cell lymphoma, unspecified (1 case), extranodal NK/T cell lymphoma, nasal type (1 case), precursor B cell lymphoblastic leukemia (1 case), or granulocytic sarcoma (1 case). XIAP was consistently expressed in the Reed-Sternberg and mononuclear Reed-Sternberg-variant cells of classical Hodgkin disease (9 of 9 cases) and the L+H Reed-Sternberg-variant cells of nodular lymphocyte predominance Hodgkin disease (3 of 3 cases). XIAP is expressed across a broad range of lymphoproliferative disorders, including classical and nodular lymphocyte predominance Hodgkin disease, diffuse large B cell lymphoma, follicular lymphoma, Burkitt lymphoma, marginal-zone and mantle cell lymphoma, and anaplastic large cell lymphoma. XIAP appears to be selectively expressed in the proliferating elements of these lymphomas. The possible prognostic and therapeutic significance of XIAP expression needs to be determined.

The Immunohistochemical Pattern of Indoleamine 2,3-Dioxygenase in Tumor Tissue Indicates the Prognosis of Patients with Diffuse Large B-Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2924-2924 ◽  
Author(s):  
Soranobu Ninomiya ◽  
Nobuhiro Kanemura ◽  
Hisashi Tsurumi ◽  
Takeshi Hara ◽  
Naoe Goto ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Poor Prognosis ◽  
Tumor Tissue ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Bulky Disease ◽  
Indoleamine 2,3 Dioxygenase ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 2924 Poster Board II-900 Introduction : Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades the essential amino acid tryptophan along the kynurenine pathway. Pro-inflammatory cytokines, such as IFN-g, induce IDO during the inflammatory response in many human cell types. The induction of IDO is synergistic in the presence of TNF-a, IL-1 or IL-6, and might be mediated by a signaling pathway from NF-κB and/or MAPKs. Furthermore, some metabolites derived from tryptophan by IDO, such as L-kynurenine, block antigen-driven specific T-cell proliferation and induce T-cell death. Thus, IDO activity might play an important role in regulation of the immune response exerted by antigen presenting cells and also provide transformed cells with a potent tool to help escape from assault by the immune system. Indeed, we have previously reported that high serum L-kynurenine level is associated with poor prognosis of diffuse large B-cell lymphoma (DLBCL) (ASH 2008 abstract 2812). Here, we investigated the IDO expression of patients with DLBCL. Patients and methods : The study protocol comprised a prospective, consecutive entry design that was approved by our Institutional Review Board. We investigated 119 patients between December 2003 and June 2008 who were histologically diagnosed with DLBCL according to the WHO classification. We performed immunohistochemical (IHC) analysis for IDO expression by mouse anti-human IDO monoclonal antibody. Patients aged <70 y received 8 cycles of either R-CHOP or R-THP-COP therapy. Each regimen consisted of rituximab (R: 375 mg/m2), cyclophosphamide (CPA: 750 mg/m2), doxorubicin (DOX) or tetrahydropyranyl-adriamycin (THP; 50 mg/m2), vincristine (VCR; 1.4 mg/m2, maximal dose 2.0 mg), and prednisolone (PSL; 100 mg daily). The R-THP-COP regimen included THP, an anthracycline derivative of DOX. Patients aged ≥70 y received 6 cycles of R-CHOP or R-THP-COP therapy. The chemotherapy cycles were repeated at 14-day intervals in patients aged <70 y, and at 21-day intervals in patients aged ≥70 y. Patients with bulky disease received radiotherapy ranging from 30 to 40 Gy. Responses to treatment were categorized as defined by Cheson et al. Results : The median age was 65.2 year (range, 24 - 88 y) and the median follow-up was 22.9 month (range, 0.60 – 55.4 mo). The IDO expression patterns were classified into 3 categories; diffuse positive, focal positive and negative patterns. The diffuse positive IDO expression in tumor tissue was found in 38 cases (32%). The focal positive and negative expression of IDO was 16 cases (13.4%) and 65 cases (54.6%), respectively. The diffuse IDO positive cells were lymphoma cells and the focal IDO positive cells were dendritic cells (DC) confirmed by IHC analysis. The CR rates of patients with diffuse positive IDO expression, focal positive and negative were 55.3%, 62.5% and 83.1%, respectively (P<0.05). The 3-year overall survival rates for patients with diffuse positive, focal positive and negative were 49.8%, 66.3% and 81.4%, respectively (p=0.001). IDO expression was not significantly associated with the classification of germinal center (GC) type nor non-GC type. Discussion : A poor prognosis of patients with positive IDO expression might suggest that local immunity in tumor tissue is depressed by increasing L-kynurenine levels. Hence, IDO expression contributes to refractory to chemotherapy for DLBCL. Interestingly, expression pattern of IDO was significantly related with response to the treatment and prognosis of DLBCL. In conclusion, IDO activity might play an important role in DLBCL and the cells which express IDO are important for the response to treatment and prognosis of this malignancy. IDO, therefore, might be a candidate of therapeutic targets for DLBCL patients who are resistance to chemotherapy. Disclosures: No relevant conflicts of interest to declare.

Comparing MicroRNA Expression In Aggressive and Indolent Non-Hodgkin Lymphomas Identifies a Prognostic Signature for Mantle Cell Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 800-800
Author(s):  
Rashmi S. Goswami ◽  
Levi Waldron ◽  
Patricia P Reis ◽  
Yali Xuan ◽  
Wei Xu ◽  
...  
Keyword(s):  
B Cell ◽  
Poor Prognosis ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Good Prognosis ◽  
Outcome Data ◽  
Training Set ◽  
Mantle Cell ◽  
Prognosis Group ◽  
Good Prognosis Group

Abstract Abstract 800 Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma (NHL) accounting for ~6% of all NHL. It is sensitive to combination chemotherapy, but remission durations are short without approaches such as stem cell transplantation (SCT). Most patients are incurable, but the clinical course is variable, with some patients succumbing quickly, while others survive >10 years. MicroRNAs (miRs) are small, non-coding RNAs that regulate gene expression by inhibiting mRNA translation. miRs are useful in the prognostic assessment of tumors, but work to date examining differences between MCL and normal lymphoid tissues, have only identified 2 miRs involved in MCL prognosis (Zhao JJ, Blood, 2010; Di Lisio L, Leukemia, 2010). We used a novel approach to identify a prognostic miR signature in MCL. We hypothesized that a miR signature defining aggressiveness can be obtained by comparing miR expression profiles of aggressive NHL with indolent NHL, and that this signature when applied to a set of MCL cases, may aid in MCL prognosis. Total RNA was extracted from 135 formalin-fixed paraffin-embedded samples obtained at primary diagnosis (Table 1). RNA from a training set of 19 indolent and 20 aggressive NHL cases was analyzed on a high-throughput quantitative real-time PCR (qRT-PCR) platform assessing the expression of 365 miRs and 3 endogenous controls (TaqMan Human MicroRNA Array v1.0: TLDA, ABI) using the DDCt method. A two-sample Wilcoxon Rank sum test corrected for false discovery rate was used to assess the significance of differential expression for each miR between aggressive and indolent NHL. The 14 most significantly differentially expressed miRs (p<0.001, FDR<0.02) were validated on an independent set of 25 indolent NHL and 19 aggressive NHL by qRT-PCR, and analyzed using the DDCt method. Univariate analysis using a one-sided t-test yielded 9 miRs that validated on the independent NHL set. Multivariable analysis demonstrated the ability of this 9 miR signature to distinguish between aggressive and indolent NHL (p<0.0001). Applying this signature to a set of 32 MCL patients with complete outcome data (Table 2) separated a poor prognosis group (median OS: 15 months, range: 4–40 months) from a good prognosis group (median OS: 88 months, range: 41–131 months) (Fig. 1). Among the 9 miRs were miR-29c, shown to have some prognostic value in MCL by Zhao et al., and miR-26a, shown to be important in MCL pathogenesis by Di Lisio et al. In light of the overlap with such recent studies, we believe the 9 miR prognostic signature we have identified may be of clinical utility. We are currently identifying mRNA targets for this miR signature and validating both the signature and the deregulated expression of these targets on a larger set of 200 MCL samples with known outcome data. Fig. 1. Psrincipal component analysis demonstrating separation of MCL cases into a good prognosis group in red (median OS: 88 months, range: 41–131 months) and a poor prognosis group in blue (median OS: 15 months, range: 4–40 months) based on expression of a 9 miR aggressiveness signature. Fig. 1. Psrincipal component analysis demonstrating separation of MCL cases into a good prognosis group in red (median OS: 88 months, range: 41–131 months) and a poor prognosis group in blue (median OS: 15 months, range: 4–40 months) based on expression of a 9 miR aggressiveness signature. Table 1. Sample breakdown Training set Number Aggressive cases Diffuse large B-cell lymphoma 5 Primary mediastinal B-cell lymphoma 5 Burkitt lymphoma 5 Atypical Burkitt 5 Indolent cases Small lymphocytic lymphoma/CLL 5 Extranodal marginal zone lymphoma 5 Follicular lymphoma Grade 1 3 Grade 2 3 Grade 3a 3 Validation set Aggressive cases Diffuse large B-cell lymphoma 7 Primary mediastinal B-cell lymphoma 5 Burkitt lymphoma 3 Atypical Burkitt 4 Indolent cases Small lymphocytic lymphoma/CLL 5 Extranodal marginal zone lymphoma 5 Follicular lymphoma Grade 1 5 Grade 2 5 Grade 3a 5 MCL cases Conventional 19 Blastoid/pleomorphic 11 Prolymphocytoid 1 Multiple lymphomatoid polyposis 1 Normal benign lymph nodes 20 TOTAL 135 Table 2. MCL clinical data Features Total % Gender Male 23 72 Female 9 28 ECOG 0 12 38 1 17 53 2-3 3 9 Stage 1 2 6 2 8 25 3 7 22 4 15 47 B symptoms 9 28 Extranodal sites 5 16 Lines of therapy 0 2 6 1 14 44 2 3 9 3 6 19 4 3 9 >4 4 13 Types of therapy Observation alone 2 6 Anthracycline-based 18 56 Rituximab 14 44 SCT 3 9 Bortezomib 3 9 Radiation 14 44 Median Range Age (yrs) 69 37–90 M-IPI score 6.6 5.3–8.7 Ki-67 (%) 25 7.5–90 Time to 1st treatment (months) 0.8 0.1–99.1 Overall survival (months) 34 4–131 Disclosures: Kuruvilla: Hoffman LaRoche: Honoraria, Research Funding; Celgene: Research Funding; Amgen: Honoraria; Otsuka: Honoraria; Genzyme: Honoraria.

scholarly journals Autologous culture model of nodal B-cell lymphoma identifies ex vivo determinants of response to bispecific antibodies

2021 ◽  
Author(s):  
Tobias Roider ◽  
Berit J. Brinkmann ◽  
Vladislav Kim ◽  
Mareike Knoll ◽  
Carolin Kolb ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
Ex Vivo ◽  
B Cell Lymphoma ◽  
Bispecific Antibodies ◽  
Cell Phenotype ◽  
Activation Markers ◽  
Culture Model

Bispecific antibodies (BsAb) can induce long-term responses in refractory and relapsed B cell lymphoma patients. Nevertheless, response rates across patients are heterogenous and the factors determining quality and duration of responses are poorly understood. In order to identify key determinants of response to BsAb, we established a primary, autologous culture model allowing us to mimic treatment with CD3xCD19 and CD3xCD20 BsAb within the lymph node microenvironment ex vivo. T cell-mediated killing of lymphoma cells and proliferation of T cells varied significantly among patients but highly correlated between BsAb targeting CD20 or CD19. Ex vivo response to BsAb was significantly associated with expansion of T cells and secretion of effector molecules, such as granzyme B and perforin, but not with expression of T cell exhaustion (e.g. PD1, TIM3) or activation markers (e.g. CD25, CD69) or formation of intercellular contacts. In addition, we identified a distinct phenotype of regulatory T cells that was linked to ex vivo response independently from T cell frequency at baseline. High expression levels of Aiolos (IKZF1), ICOS and CXCR5 were positively associated with ex vivo response, whereas strong expression of Helios (IKZF2) had unfavorable impact on ex vivo response to BsAb. Furthermore, we demonstrated that lenalidomide, nivolumab and atezolizumab improved ex vivo response to BsAb by potentiating T cell effector functions. In summary, our ex vivo study identifies a distinct regulatory T cell phenotype as potential contributor to treatment failure of BsAb, and suggests drug combinations of high clinical relevance that could improve the efficacy of BsAb.

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