Management of T-Cell Large Granular Lymphocyte Leukemia with Methotrexate or Cyclophosphamide

Abstract Background. T-Cell Large Granular Lymphocyte Leukemia (T-LGL Leukemia) is an extremely rare lymphoproliferative disorder which can originate from either mature T cells (CD3+) or natural killer cells (CD3-). T-LGL leukemia is a slowly progressing disease, rarely presenting with an aggressive course and in general patients have prolonged survival. Treatment is commonly monotherapy with methotrexate (with or without prednisone), cyclosporine, or cyclophosphamide. Herein we review our experience with the management of T-LGL in the last 15 years. Patients and Methods. We conducted a retrospective cohort study of all patients diagnosed with T-LGL at our center between 2000 and 2015. Patients were included if they had a positive study for T-Cell Receptor gene rearrangement. Response was evaluated using the criteria of Loughran et al (Leukemia 2015). Data was analyzed using descriptive statistics. Results. We included 23 patients, (16 male). All of the patients were caucasian with the exception of two. The average age at diagnosis is 65.1 years. Patients were treated for symptomatic cytopenias or splenomegaly with transfusions and/or chemotherapy. Six patients did not need any treatment. Fourteen of the 23 patients were treated with oral methotrexate monotherapy. The methotrexate dose ranged from 5mg/week to 15mg/week orally. Seven patients had a complete response, 2 had a partial response, 3 patients failed treatment, 1 patient was not evaluable, and 1 was stable. Four patients were treated with methotrexate and prednisone. Two patients obtained a complete response, with 1 partial response, and 1 patient was not evaluable due to the short duration of the prescription. Nine patients were treated with oral cyclophosphamide at doses of 50mg or 100mg po daily. Four patients achieved a complete response, 2 patients achieved a partial response, while the other 3 patients did not respond. Only 2 patients were treated with oral cyclosporine, at 400mg/day and at 500mg/day. One patient failed treatment while the other is still on therapy. Two patients died while on the study at 22 and 42 months, both deaths were due to other illnesses not associated with T-LGL Leukemia. The median time since diagnosis for the remaining patients is 41 months. Conclusion. T-LGL is a rare lymphoproliferative disorder. Most patients responded to simple oral therapy with methotrexate or cyclophosphamide and patients generally have prolonged survivals. Disclosures Lazo-Langner: Bayer: Honoraria; Pfizer: Honoraria. Kovacs:Daiichi Sankyo Pharma: Research Funding; LEO Pharma: Honoraria; Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

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Large Granular Lymphocyte Leukemia: Case Report of Chronic Neutropenia and Rheumatoid Arthritis-like Symptoms in a Child

Pediatric and Developmental Pathology ◽

10.1007/s100240010126 ◽

2001 ◽

Vol 4 (1) ◽

pp. 94-99 ◽

Cited By ~ 4

Author(s):

Carol A. Blanchong ◽

Randal Olshefski ◽

Samir Kahwash

Keyword(s):

Rheumatoid Arthritis ◽

T Cell ◽

Receptor Gene ◽

Lymphoproliferative Disorders ◽

Large Granular Lymphocyte ◽

Large Granular Lymphocytes ◽

Large Granular Lymphocyte Leukemia ◽

Granular Lymphocytes ◽

Chronic Neutropenia ◽

Lgl Leukemia

Lymphoproliferative disorders of large granular lymphocytes (LGL) are heterogeneous, with a clinical/pathologic spectrum ranging from a benign polyclonal expansion to an aggressive clonal disease. Often these lymphoproliferative disorders are associated with autoimmune disease. The clonal form of the disorder, LGL leukemia, typically occurs in older adults with a median age of 55 years at diagnosis. Pediatric cases are referred to in review articles; however, no detailed reports of T-cell LGL leukemia in children exist. This report illustrates a case of a child who presented initially at age 2 and 1/2 years with psoriasis, juvenile rheumatoid arthritis-like symptoms, and neutropenia. Bone marrow examinations obtained throughout his course have demonstrated progressive hypercellularity with increased reticulin fibers and replacement of the normal marrow elements by lymphocytes, which were later identified as large granular lymphocytes. Further testing with immunophenotyping by flow cytometry and T-cell receptor gene rearrangement studies revealed a monoclonal proliferation of large granular lymphocytes and confirmed a diagnosis of LGL leukemia. Although rare, large granular lymphocyte leukemia should be included in the differential diagnosis of chronic neutropenia in children.

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High Resolution Karyotyping of Large Granular Lymphocyte Leukemia by SNP Arrays Reveals Clonal Defects Leading to LOH at Loci Integral to Lymphocyte Function.

Blood ◽

10.1182/blood.v112.11.1513.1513 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1513-1513

Author(s):

Aaron D. Viny ◽

Hideki Makashima ◽

Jungwon Huh ◽

Karl S. Theil ◽

Lukasz Gondek ◽

...

Keyword(s):

T Cell ◽

Copy Number ◽

Chromosomal Abnormalities ◽

Germ Line ◽

Clonal Expansion ◽

Large Granular Lymphocyte ◽

Copy Number Loss ◽

Snp Arrays ◽

Large Granular Lymphocyte Leukemia ◽

Lgl Leukemia

Abstract Large granular lymphocyte leukemia (LGL leukemia) is a semiautonomous clonal lymphoproliferation of cytotoxic T cells associated with various immune cytopenias. Within the spectrum of acquired immune-mediated bone marrow failure states, LGL leukemia can serve as monoclonal model of usually polyclonal T cell-mediated pathology. Mechanisms of unopposed clonal expansion of LGL cells in many aspects resemble true lymphoma and are not well understood. In addition to its reactive character, intrinsic clonal defects may be present in some patient with LGL, in particular those with more pronounced lymphoproliferative features. However, unlike in B-cell lymphomas, recurrent chromosomal abnormalities have not been frequently identified in LGL leukemia using traditional metaphase karyotyping techniques. We have applied Affymetrix 250K single nucleotide polymorphism-arrays (SNP-A) and 6.0 SNP-A in 28 patients with LGL leukemia, to elicit a far higher resolution of chromosomal content through genomic mapping of individual SNP and respective copy number analysis in LGL leukemia. SNP-A based cytogenetics have been applied successfully to MDS patients and has increased prognostic reliability. Blood mononuclear cells containing high proportion of clonal cells as determined by TCR Vβ flow cytometry were used as a source of DNA. For comparison, a large number of control blood and marrow specimens (N=119 for 6.0 and 124 for 250K SNP arrays) were analyzed. Data were processed using Genotyping Console v2.1 software (Affymetrix, Santa Clara, CA). After exclusion of known copy number variants (CNV) referenced in public databases and our own set of 178 normal controls, we found distinct chromosomal changes in 16/28 (57%) of LGL leukemia patients. Consensus regions of deletion/gain or uniparental disomy (UPD) were identified. The most common abnormalities included either UPD or copy number loss of chromosome 3q21.2–q21.31, which was identified in 6 (21%) patients. This region harbors CD86, the gene encoding the B7.2 protein responsible for T cell activation and regulation through costimulatory mechanisms. Copy number loss/UPD was also identified at chromosome 1p31.1–p32.3 in 4 (18%) patients. Interestingly, copy number gain in this same region was identified in 2 (9%) patients suggesting that this region may correspond to either a new, infrequent germ line encoded CNV or represents a somatic microdeletion. Recent studies indicated a role for SIL/SCL, which resides at this locus, in V(D)J recombination, lymphocyte development, and maturation. Additional conserved chromosomal abnormalities included copy number gains in 14q (11%) and copy number loss at 11p15 (14%), all possibly representing germ line or somatic CNV physiologically acquired during lymphocyte ontogenesis. We compared chromosomal lesions identified in our LGL cohort with clinical features including age, presence of neutropenia, anemia, thrombocytopenia, splenomegaly, immunophenotype, and degree of clonal expansion. No difference in clinical course was found between patients with and without cytogenetic abnormalities with regard to type and severity of cytopenias or size of the LGL clone. However, patients with 1p31.1–p32.3 deletions were found to have lesser degree of neutropenia compared to patients without 1p31.1–p32.3 deletions (p<0.001). While these data may reflect chromosomal variants and random somatic abnormalities, the recurrent loss of heterozygosity and gains within several loci with known regulatory function for lymphocyte biology suggests the involvement of these defects in the mechanism of clonal evolution.

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Clonotype Switching Indicates Propensity for Clonal Outgrowth From Diverse Components of the T Cell Repertoire In T Cell Large Granular Lymphocyte Leukemia.

Blood ◽

10.1182/blood.v116.21.1171.1171 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1171-1171

Author(s):

Michael J. Clemente ◽

Marcin W. Wlodarski ◽

Aaron D. Viny ◽

Mohammed Shaik ◽

Nelli Bejanyan ◽

...

Keyword(s):

Flow Cytometry ◽

T Cell ◽

Autoimmune Disease ◽

Significant Proportion ◽

Surrogate Marker ◽

The Body ◽

Large Granular Lymphocyte ◽

Large Granular Lymphocyte Leukemia ◽

Flow Cytometric ◽

Lgl Leukemia

Abstract Abstract 1171 T cell large granular lymphocyte leukemia (T-LGLL) is characterized by the chronic proliferation of cytotoxic T lymphocytes (CTL) and is often associated with lineage-restricted cytopenias, autoimmune disease and B cell dyscrasias. In many patients clinical features of a true leukemia are absent. Lack of transformation, absence of progressive increase in blood counts, and a paucity of recurrent chromosomal defects or mutations clearly distinguish LGL from typical leukemic development. Thus, some forms of T-LGLL resemble more of a reactive process and possibly represent an extreme pole of oligo- or polyclonal immune reactions to viruses, autoantigens, or perhaps even exaggerated immune tumor surveillance. We have shown that a highly skewed T cell receptor (TCR) variable beta (Vβ) repertoire is strongly associated with monoclonality of TCR CDR3 regions by sequencing and therefore, detection of a Vβ expansion by flow cytometric clonotyping can serve as a surrogate marker for the presence of a clonal CTL process. Flow cytometric Vβ typing offers an opportunity to study the dynamics of the CTL clonal progression during therapy and throughout the clinical course of disease. We studied 124 patients who not only met the WHO guidelines for the diagnosis of T-LGLL but also show skewing of the Vβ spectrum by flow cytometry consistent with the mono/oligoclonal process persistent for over 6 months; 100% of cases demonstrated both TCRγ rearrangement and abnormal CTL population by flow cytometry. LGL count >900/μL was present in 73% of patients (mean 2513±3571 cells/μL). A pathologic clonal Vβ expansion was defined as > mean + 2SD of controls (n=65). Expansions identified by the Vβ panel were present in 92% (mean clone size 55±28%) and 2% had a borderline expansion (within 20% of 2SD) and 3% a δ/γ CD8+ TCR expansion. In 6% the Vβ expanded clone expressed CD4. Absolute clone count (ACC) was calculated by the Vβ contribution multiplied by the absolute CD8 (or CD4) count per μL of blood. ACC correlated well with LGL count (p<.0001, R2=.58). Clinically, patients presented with anemia (25%), neutropenia (9%), pancytopenia (19%), thrombocytopenia (3%), or multi-lineage cytopenia (29%), and 15% of patients were asymptomatic. In order to assess clonal kinetics, 62 of these patients were available for serial Vβ measurements with a follow up range of 0.5–8 years. Paired statistical analysis of clonal dynamics pre and post therapy (cyclophosphamide, alemtuzumab, methotrexate or cyclosporine) demonstrated a significant decrease in ACC between responders and refractory patients (p=.024). Unexpectedly, some patients displayed a change in the dominant clone as demonstrated by a switch in the major clonal Vβ T cell population, i.e. “clonotype switch.” Overall, 32% exhibited a clonotype switch during the study period, while others exhibited the persistence of multiple clones (22%); in 46% the initially diagnosed Vβ monoclonal expansion persisted. Those with multiple clones were more likely to change clonal dominance (p=.05). Clonotype switch was observed in both in relapsed and in refractory patients, and also was frequently accompanied by a change in clinical hematologic features. Significant absolute lymphocytosis (>4000 lymphocytes/μL) was present in 34/124 (27%) patients while 66 had normal lymphocyte counts and 24 were lymphopenic. Of the patients followed serially who clonotype switched, only 3/20 (15%) had absolute lymphocytosis, suggesting that 2 distinct subtypes of T-LGLL may exist. Patients with high lymphocyte and LGL counts may represent a true leukemic process, are less likely to have associated autoimmune disease or second malignancy, and their dominant clone is stable, suggestive of a single transformed precursor. In contrast, in patients with clonal CTL expansions not associated with absolute lymphocytosis, clonotype switching is difficult to reconcile with a true autonomous leukemic process. In sum, our results suggest that in a significant proportion of patients with T-LGL leukemia, the propensity for clonal CTL dominance is not inherent to an aberrant molecular event within the abnormal CTL clone but may rather be related to extrinsic chronic antigenic drive and immune dysregulation. Furthermore, our results lend credence to the body of evidence suggesting that T-LGL leukemia may not, in many instances, be a true leukemia, and may best be classified as T-LGL lymphoproliferation. Disclosures: No relevant conflicts of interest to declare.

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Literature Review of All Cases of Aggressive T-Cell Large Granular Lymphocytic Leukemia Cases and Report of an Additional Case

Blood ◽

10.1182/blood-2018-99-111726 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5421-5421

Author(s):

Vanessa Brunet ◽

Michel Pavic ◽

Sofia Marouan ◽

Isabelle Fleury ◽

Jean-Francois Castilloux

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Lymphoproliferative Disorder ◽

Clinical Presentation ◽

Nk Cell ◽

Leukemic Cells ◽

Cell Leukemia ◽

Advisory Committees ◽

Lgl Leukemia

Abstract Large granular lymphocyte (LGL) leukemia is a spectrum of rare lymphoproliferative disorders, classified into T-cell LGL leukemia, chronic lymphoproliferative disorder of NK-cells and aggressive NK-cell leukemia; chronic NK-cell leukemia is a provisional diagnosis. However, we identified fourteen cases of aggressive T-LGL leukemia retrieved in the literature. Considering this unusual and rare clinical presentation, we are reporting a literature review and presenting an additional case. Leukemic cells of T-LGL leukemia have a characteristic phenotype (CD3+CD8+CD16+CD57+) and show clonal TCR gene rearrangement, while leukemic cells of aggressive NK cell leukemia show a distinguishable phenotype (CD3-CD4-CD8-CD16+CD56+CD57-) and are EBV-related. In contrast with the aggressive NK cell leukemia, the chronic lymphoproliferative disorder of T-cell is not EBV-associated and has a distinguishable immunophenotype (CD16+CD56−CD57+). While T-LGL leukemia and chronic lymphoproliferative disorder of NK-cells have a more chronic disease (years), mainly reported with autoimmune disease (rheumatoid arthritis), numerous infections due to neutropenia and a mild-to-moderate splenomegaly, aggressive NK-cell leukemia is characterized by systemic manifestations and a disseminated disease after a few weeks of presentation despite treatment instauration. In contrast to the T-LGL leukemia, aggressive T-LGL leukemia has a clinical presentation similar to the aggressive NK-cell leukemia, characterized by constitutional symptoms, rapidly progressive hepatosplenomegaly, cytopenia and organ infiltration. The atypical clinical presentation and pathological findings of the aggressive T-LGL leukemia explain the diagnostic challenge of this entity for clinicians. In fact, cases of aggressive T- LGL leukemia retrieved atypical size, irregular nuclei and atypical immunophenotype. Some cases had features similar to those described for patients with NK-cell leukemia (CD56+CD57-) while others did not present neither NK nor T-cell classical immunophenotype (CD56-57-). Facing the heterogeneity of aggressive LGL leukemia, the rapidly evolutive disease (multi-organic infiltration) and the absence of randomized trials on large numbers of patients, no consensus on the treatment approach exists. (Table 1) Our patient presented, at the age of 24 yo, with transitory and autonomous resolution of hepatosplenomegaly and pancytopenia. Almost 30 years later, the patient developed a similar and persistent episode, which lead to a diagnosis of aggressive T-cell LGL leukemia. Was this first episode the early and indolent presentation of his T- LGL leukemia or was it only related to an indolent and transitory etiology? Considering the clinical evolution of previously reported case and of our patient, LGL leukemia tends to evolve in many ways; resolution, indolent and chronic or aggressive evolution and transformation into a lymphoma. As the cases retrieved in literature, the diagnosis of our patient was complicated by atypical clinical presentation and unusual pathological findings; massive medullary involvement without real images of intra-sinusal lymphocytosis and atypical T- LGL based on their small-medium size with slightly irregular nuclei and the lack of expression of CD56/CD57. Facing the heterogeneity of treatments attempted for aggressive T-LGL leukemia and their unpredictable response, we believe that the treatments given to our patient were consistent with the current literature and did not add an additional mortality risk (3 cycles of CHOP, 4 cycles of ESHAP, methotrexate, splenectomy). As reported in literature, even though our patient was treated with varying regimens, his disease rapidly evolved into a multi-organic infiltration (skin, lungs, liver, kidney, facial cranial nerves, conus medullaris and bone marrow involvement) Large granular lymphocyte (LGL) leukemia represent a spectrum of indolent and aggressive diseases, whereby an indolent form can evolve into an aggressive form. Aggressive T-cell LGL leukemia are characterized by a multisystem disease, an atypical immunophenotype (CD56-CD57- or CD56+CD57-) and are associated with an uncertainty regarding therapeutics.Our case report of an aggressive T-cell LGL leukemia adds to the few available studies on the subject. Disclosures Pavic: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Phase II Window Study of Pembrolizumab in Untreated B-Cell Non-Hodgkin Lymphoproliferative Diseases

Blood ◽

10.1182/blood-2019-124984 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5258-5258

Author(s):

Ajay K. Gopal ◽

Adam Greenbaum ◽

Ryan C. Lynch ◽

Edus H. Warren ◽

Chaitra S. Ujjani ◽

...

Keyword(s):

T Cell ◽

Partial Response ◽

B Cell ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Response Rate ◽

Progression Free Survival ◽

Response Assessment ◽

Complete Response ◽

Non Hodgkin Lymphoma

INTRODUCTION While chemoimmunotherapy is effective in indolent B-cell non-Hodgkin lymphoma (iBCL), most patients are older and may benefit from a chemotherapy-free approach. Pembrolizumab is an immune checkpoint inhibitor which blocks the PD-1 receptor. Upon chronic antigen stimulation, T-cells can lose their anti-tumor activity due to PD-1 signaling. Multiple in vitro and in vivo studies have demonstrated that blockade of PD-1 can reverse the T-cell dysfunction induced by the tumor microenvironment. Pembrolizumab has shown an excellent safety and toxicity profile. Pembrolizumab as a single agent is FDA approved for numerous solid tumors and some lymphoma subtypes including Hodgkin lymphoma and primary mediastinal B-cell lymphoma. PD-1 inhibitors have also shown activity in the relapsed/refractory iBCL with overall responses reported to range from 10 to 60% (Ding et al., 2017; Lesokhin et al., 2016; Nastoupil et al., 2017a). However, the overwhelming majority of the patients in these studies had received prior chemotherapy. Patients with untreated iBCL have a relatively intact immune system and may have a greater capacity to mount an effective anti-tumor immune response upon reversal of T-cell dysfunction. OBJECTIVES The primary objective is evaluate the efficacy of pembrolizumab as monotherapy for patients with untreated iBCL based on ORR measured at the end of a 6-cycle treatment period. Secondary objective include: Safety and toxicity.Efficacy including complete response, clinical benefit rate (complete response + partial response + stable disease) ≥6 months, time to next therapy, progression-free survival, and duration of response. SUBJECTS AND METHODS Patients ≥ 18 years of age with previously untreated radiographically measurable follicular or marginal zone lymphoma with an indication for treatment are included. These indications include significant symptoms, end organ damage, cytopenias, or steady progression. Major exclusions include known autoimmune disease, major organ dysfunction, or ECOG ≥ 2. Treatment consists of 200 mg pembrolizumab IV on day 1 of each 21-day cycle. Initial response assessment occurs after 6 cycles. Patients with a complete or partial response can remain on the trial. Patients who have stable disease or progressive disease and are asymptomatic (excluding hyperprogression) will receive 3 additional cycles and then will be restaged to account for a delayed response. Those patients with a complete or partial response after those additional cycles can remain on the trial. Subsequently, response assessment occurs every 3 cycles. Patients without progressive disease or unacceptable toxicity are able to continue up to 18 cycles. Up to 33 patients will be enrolled, and follow-up may continue for an additional 2 years. STATISTICAL METHODS The primary efficacy endpoint is the overall response rate (CR + PR). Secondary endpoints include duration of response, progression free survival, and time to next therapy (see treatment schema). A sample size of 33 participants is planned to provide 80% power at the 5% significance level to distinguish the observed overall response rate from a true rate of ≥ 40% versus ≤ 20%) using a Simon 2-stage minimax design. The trial will be terminated early if fewer than 5 of the first 18 patients have a response. The thresholds used in this design are based on what is considered to be a clinically meaningful response rate with a novel agent with very low rates of adverse events and toxicity compared to standard regimens. This response rate threshold is also higher than what has been observed using anti-PD-1 therapy in the relapsed/refractory setting. RECRUITMENT Three patients have been accrued to the study. To date, all patients have remained on study with no grade 3-5 adverse events. CORRELATIVE STUDIES Given that pembrolizumab is known to modulate the tumor immune microenvironment, we are also performing clinical correlates on a companion protocol. Using several 22 color flow cytometry panels and 6-color multiplex immunohistochemistry, we will analyze pre- and post-treatment lymph nodes and peripheral blood. These studies will examine over 50 populations of immune cells in addition to T-cell activation/exhaustion markers such as PD-1, TIM-3, LAG-3, CTLA-4, and PD-L1. TRIAL REGISTRATION Clinicaltrials.gov (NCT03498612). Funding for both the trial and correlative studies has been provided by Merck. Figure Disclosures Gopal: Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding. Lynch:Rhizen Pharmaceuticals S.A: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; T.G. Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Juno Therapeutics: Research Funding. Ujjani:Pharmacyclics: Honoraria; PCYC: Research Funding; Astrazeneca: Consultancy; Atara: Consultancy; Gilead: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding. Shadman:ADC Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Sound Biologics: Consultancy; Mustang Bio: Research Funding; TG Therapeutic: Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; Gilead: Consultancy, Research Funding; Celgene: Research Funding; AbbVie: Consultancy, Research Funding; Acerta Pharma: Research Funding; BeiGene: Research Funding; Sunesis: Research Funding; Astra Zeneca: Consultancy; Atara Biotherapeutics: Consultancy. Smith:Denovo Biopharma: Research Funding; Incyte Corporation: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Ignyta (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding; Ayala (spouse): Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Fromm:Merck, Inc.: Research Funding. Shustov:Seattle Genetics, Inc.: Research Funding. OffLabel Disclosure: Pembrolizumab for the treatment of indolent non-Hodgkin lymphoma

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Large Granular Lymphocyte Leukemia

Cancer Control ◽

10.1177/107327489800500103 ◽

1998 ◽

Vol 5 (1) ◽

pp. 25-33 ◽

Cited By ~ 53

Author(s):

Thierry Lamy ◽

Thomas P. Loughran

Keyword(s):

T Cell ◽

Fas Ligand ◽

Nk Cell ◽

Cytotoxic T Cells ◽

Receptor Gene ◽

Cell Lineage ◽

Constitutive Expression ◽

Large Granular Lymphocyte ◽

Leukemic Cells ◽

Lgl Leukemia

Background: Clonal diseases of large granular lymphocyte (LGL) disorders can arise from a CD3+ T-cell lineage or from a CD3– NK-cell lineage. CD3+ LGL leukemia is the most frequent form of LGL leukemia and is a distinct entity by FAB and REAL classifications. Methods: The clinical course, biological features, and recent data on pathogenesis of CD3+ LGL leukemia are reviewed. The spectrum of differential diagnosis is described. Results: T-LGL leukemia affects elderly people. Approximately 60% of patients are symptomatic; recurrent infections secondary to chronic neutropenia, anemia, and rheumatoid arthritis are the main clinical features. The most common phenotype is CD3+, CD8+, CD57+. Clonality is detected by clonal rearrangement of the T-cell receptor gene. Clinical and molecular remission can be obtained with oral low-dose methotrexate. Serologic findings show frequent reactivity to the BA21 epitope of HTLV-I env p21e, suggesting that a cellular or retroviral protein with homology to BA21 may be important in pathogenesis. Clonal expansion may be facilitated by IL-12 and IL-15 lymphokines. Constitutive expression of Fas ligand by leukemic LGLs support the hypothesis that leukemic cells arise from antigen-activated cytotoxic T cells. Leukemic LGLs express a multidrug-resistance phenotype that could partly explain the chemoresistance observed in aggressive cases. Conclusions: CD3+ LGL leukemia is a distinct lymphoproliferative T-cell disorder with specific clinicobiological aspects. The clinical spectrum of LGL proliferations is wide and immunophenotypic, and genotypic studies are needed to establish the diagnosis.

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The other T-cell receptor gene

Science ◽

10.1126/science.6729474 ◽

1984 ◽

Vol 225 (4658) ◽

pp. 155-155

Author(s):

J. Marx

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Receptor Gene ◽

Cell Receptor ◽

The Other ◽

T Cell Receptor Gene ◽

Cell Receptor Gene

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Single Cell Profiling Reveals Unique CXCL13 Positive T Cell Subsets in the Tumor Microenvironment of Lymphocyte Rich Classic Hodgkin Lymphoma

Blood ◽

10.1182/blood-2020-134929 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 32-33

Author(s):

Tomohiro Aoki ◽

Lauren C. Chong ◽

Katsuyoshi Takata ◽

Katy Milne ◽

Elizabeth Chavez ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Single Cell ◽

Immune Cells ◽

Research Funding ◽

Immune Cell ◽

Expression Patterns ◽

The Other ◽

Tfh Cells

Introduction: Classic Hodgkin lymphoma (CHL) features a unique crosstalk between malignant cells and different types of normal immune cells in the tumor-microenvironment (TME). On the basis of histomorphologic and immunophenotypic features of the malignant Hodgkin and Reed-Sternberg (HRS) cells and infiltrating immune cells, four histological subtypes of CHL are recognized: Nodular sclerosing (NS), Mixed cellularity, Lymphocyte-rich (LR) and Lymphocyte-depleted CHL. Recently, our group described the high abundance of various types of immunosuppressive CD4+ T cells including LAG3+ and/or CTLA4+ cells in the TME of CHL using single cell RNA sequencing (scRNAseq). However, the TME of LR-CHL has not been well characterized due to the rarity of the disease. In this study, we aimed at characterizing the immune cell profile of LR-CHL at single cell resolution. METHODS: We performed scRNAseq on cell suspensions collected from lymph nodes of 28 primary CHL patients, including 11 NS, 9 MC and 8 LR samples, with 5 reactive lymph nodes (RLN) serving as normal controls. We merged the expression data from all cells (CHL and RLN) and performed batch correction and normalization. We also performed single- and multi-color immunohistochemistry (IHC) on tissue microarray (TMA) slides from the same patients. In addition, an independent validation cohort of 31 pre-treatment LR-CHL samples assembled on a TMA, were also evaluated by IHC. Results: A total of 23 phenotypic cell clusters were identified using unsupervised clustering (PhenoGraph). We assigned each cluster to a cell type based on the expression of genes described in published transcriptome data of sorted immune cells and known canonical markers. While most immune cell phenotypes were present in all pathological subtypes, we observed a lower abundance of regulatory T cells (Tregs) in LR-CHL in comparison to the other CHL subtypes. Conversely, we found that B cells were enriched in LR-CHL when compared to the other subtypes and specifically, all four naïve B-cell clusters were quantitatively dominated by cells derived from the LR-CHL samples. T follicular helper (TFH) cells support antibody response and differentiation of B cells. Our data show the preferential enrichment of TFH in LR-CHL as compared to other CHL subtypes, but TFH cells were still less frequent compared to RLN. Of note, Chemokine C-X-C motif ligand 13 (CXCL13) was identified as the most up-regulated gene in LR compared to RLN. CXCL13, which is a ligand of C-X-C motif receptor 5 (CXCR5) is well known as a B-cell attractant via the CXCR5-CXCL13 axis. Analyzing co-expression patterns on the single cell level revealed that the majority of CXCL13+ T cells co-expressed PD-1 and ICOS, which is known as a universal TFH marker, but co-expression of CXCR5, another common TFH marker, was variable. Notably, classical TFH cells co-expressing CXCR5 and PD-1 were significantly enriched in RLN, whereas PD-1+ CXCL13+ CXCR5- CD4+ T cells were significantly enriched in LR-CHL. These co-expression patterns were validated using flow cytometry. Moreover, the expression of CXCR5 on naïve B cells in the TME was increased in LR-CHL compared to the other CHL subtypes We next sought to understand the spatial relationship between CXCL13+ T cells and malignant HRS cells. IHC of all cases revealed that CXCL13+ T cells were significantly enriched in the LR-CHL TME compared to other subtypes of CHL, and 46% of the LR-CHL cases showed CXCL13+ T cell rosettes closely surrounding HRS cells. Since PD-1+ T cell rosettes are known as a specific feature of LR-CHL, we confirmed co-expression of PD-1 in the rosetting cells by IHC in these cases. Conclusions: Our results reveal a unique TME composition in LR-CHL. LR-CHL seems to be distinctly characterized among the CHL subtypes by enrichment of CXCR5+ naïve B cells and CD4+ CXCL13+ PD-1+ T cells, indicating the importance of the CXCR5-CXCL13 axis in the pathogenesis of LR-CHL. Figure Disclosures Savage: BeiGene: Other: Steering Committee; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy. Scott:Janssen: Consultancy, Research Funding; Celgene: Consultancy; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy. Steidl:AbbVie: Consultancy; Roche: Consultancy; Curis Inc: Consultancy; Juno Therapeutics: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Research Funding.

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