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Terraflow, a New High Parameter Data Analysis Tool, Reveals Systemic T-Cell Exhaustion and Dysfunctional Cytokine Production in Classical Hodgkin Lymphoma [Meeting Abstract]

Freeman, D; Lam, L; Li, T; Alexandre, J; Raphael, B G; Kaminetzky, D; Ruan, J; Chattopadhyay, P; Diefenbach, C S
Background Classical Hodgkin lymphoma (cHL) is characterized by rare, malignant Hodgkin/Reed Sternberg (HRS) cells that shape their microenvironment (TME) to inhibit anti-tumor immune response. Systemic immune dysregulation may influence treatment response and toxicity, but the systemic influence of the TME is less well described. The wide variety of proteins measured in high-parmater flow cytometry make it a powerful tool for immune monitoring, but presents challenges in immuno-monitoring. Combinatorial expression of these proteins defines cell types that may influence disease. TerraFlow is a fully automated data analysis platform that evaluates millions of phenotypes and selects the populations that best predict clinical variables. The analysis can be performed using classical Boolean gates or a non-gating approach that approximates gates without using manual thresholds, allowing immunophenotypes to be comprehensively surveyed for disease associations. The platform was used to find phenotypes that discriminate healthy versus cHL patients (AUC = 1) and pre versus post treatment patient phenotypes(AUC = 0.79). Methods Human Subjects: Informed consent was obtained from cHL patients (N=44) treated at the Perlmutter Cancer Center (PCC) at NYU Langone Health and New York Presbyterian Weil Cornell (NYP) between 2011 and 2016. Blood samples were drawn at multiple time-points, for this study pre-treatment and 3 month post-treatment samples were used. Age-matched, cryopreserved healthy donor PBMC (n=25) were obtained from STEMCELL Technologies (Cambridge, MA).Patient-derived blood was processed for isolation of PBMC, stained analyzed on a Symphony Flow Cytometer (BD Biosciences, San Jose, CA). Analysis: Data was analyzed using an original platform called terraFlow. Many immune cell subsets are defined by the combinations of proteins they express. TerraFlow systematically evaluates millions of cell types by generating every possible combination of 1 to 5 markers. A network-based algorithm then selects the "best" phenotype from each set of inter-related combinations based on statistical power and ease of interpretation. Each phenotype is defined using a minimal gating strategy that can be replicated in a diagnostic panel or cell sorter. Together, phenotypes describe all the major differences between patient groups. A new platform developed by Epistemic AI was used to mine scientific literature and interpret selected phenotypes. Results We observed clear perturbations in the cHL systemic T-cell compartment pre-treatment as shown in Figure 1. These include higher levels of activated (CD278+), exhausted (CD366+, PD1+, CD152+), and suppressive (GITR+) T-cells compared to healthy donors, and diminished levels of T-cells producing effector cytokines (like IFNgamma and IL4). Subsets of cytokine-producing cells that co-express markers of exhaustion (i.e., TNF+ CD366+ cells) are also elevated in cHL patients. Finally, T-cells expressing CD127 a receptor for IL7 involved in homeostatic renewal of cells and observed on naive and central memory T-cells are reduced. Taken together, these findings suggest that in cHL the systemic T-cell compartment is shifted toward a more exhausted profile, and away from less differentiated cells, with the potential for self-renewal. Our data also demonstrates a shift from T-helper 1 and T-helper 2 type toward T-helper 17 cells suggesting that T-cell effector function may be reduced. Conclusion Using a novel data analysis platform, TerraFlow we demonstrate dysregulation in systemic T cell function in cHL patients pre-treatment that persists within 3 months of completing therapy. Associations of phenotypes with clinical variables, and post-treatment phenotypes will be described in detail at the meeting. Our results detail new immunotherapy and biomarker research targets, and suggest novel strategies for combination therapies. [Formula presented] Disclosures: Li: BD Bioscience: Current Employment. Ruan: Kite Pharma: Consultancy; AstraZeneca: Research Funding; BMS: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seagen: Consultancy. Diefenbach: Incyte: Research Funding; Trillium: Research Funding; Celgene: Research Funding; IGM Biosciences: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Gilead: Current equity holder in publicly-traded company; AbbVie: Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; MEI: Consultancy, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; IMab: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding.
ISSN: 1528-0020
CID: 5104372

Impaired Humoral Immunity to SARS-CoV-2 Vaccination in Non-Hodgkin Lymphoma and CLL Patients

Diefenbach, Catherine; Caro, Jessica; Koide, Akiko; Grossbard, Michael; Goldberg, Judith D; Raphael, Bruce; Hymes, Kenneth; Moskovits, Tibor; Kreditor, Maxim; Kaminetzky, David; Fleur-Lominy, Shella Saint; Choi, Jun; Thannickal, Sara A; Stapleford, Kenneth A; Koide, Shohei
Patients with hematologic malignancies are a high priority for SARS-CoV-2 vaccination, yet the benefit they will derive is uncertain. We investigated the humoral response to vaccination in 53 non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or CLL patients. Peripheral blood was obtained 2 weeks after first vaccination and 6 weeks after second vaccination for antibody profiling using the multiplex bead-binding assay. Serum IgG, IgA, and IgM antibody levels to the spike specific receptor binding domain (RBD) were evaluated as a measure of response. Subsequently, antibody-positive serum were assayed for neutralization capacity against authentic SARS-CoV-2. Histology was 68% lymphoma and 32% CLL; groups were: patients receiving anti-CD20-based therapy (45%), monitored with disease (28%), receiving BTK inhibitors (19%), or chemotherapy (all HL) (8%). SARS-CoV-2 specific RBD IgG antibody response was decreased across all NHL and CLL groups: 25%, 73%, and 40%, respectively. Antibody IgG titers were significantly reduced (p < 0.001) for CD20 treated and targeted therapy patients, and (p = 0.003) for monitored patients. In 94% of patients evaluated after first and second vaccination, antibody titers did not significantly boost after second vaccination. Only 13% of CD20 treated and 13% of monitored patients generated neutralizing antibodies to SARS-CoV-2 with ICD50s 135 to 1767, and 445 and > 10240. This data has profound implications given the current guidance relaxing masking restrictions and for timing of vaccinations. Unless immunity is confirmed with laboratory testing, these patients should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals.
PMID: 34100025
ISSN: n/a
CID: 4899722

Microbial dysbiosis is associated with aggressive histology and adverse clinical outcome in B-cell non-Hodgkin lymphoma

Diefenbach, Catherine S; Peters, Brandilyn A; Li, Huilin; Raphael, Bruce; Moskovits, Tibor; Hymes, Kenneth; Schluter, Jonas; Chen, J; Bennani, N Nora; Witzig, Thomas E; Ahn, Jiyoung
B-cell non-Hodgkin lymphoma cell survival depends on poorly understood immune evasion mechanisms. In melanoma, the composition of the gut microbiota (GMB) is associated with immune system regulation and response to immunotherapy. We investigated the association of GMB composition and diversity with lymphoma biology and treatment outcome. Patients with diffuse large B-cell lymphoma (DLBCL), marginal zone (MZL), and follicular lymphoma (FL) were recruited at Mayo Clinic, Minnesota, and Perlmutter Cancer Center, NYU Langone Health. The pretreatment GMB was analyzed using 16S ribosomal RNA gene sequencing. We examined GMB compositions in 3 contexts: lymphoma patients (51) compared with healthy controls (58), aggressive (DLBCL) (8) compared with indolent (FL, MZL) (18), and the association of GMB with immunochemotherapy treatment outcomes (8 responders, 6 nonresponders). Respectively, we found that the pretreatment GMB in lymphoma patients had a distinct composition compared with healthy controls (P < .001); GMB compositions in DLBCL patients were significantly different than indolent patients (P = .01) with a trend toward reduced microbial diversity in DLBCL patients (P = .08); and pretreatment GMB diversity and composition were significant predictors of treatment responses (P = .01). The impact of these pilot results is limited by our small sample size, and should be considered a proof of principle. If validated, our results could lead toward improved treatment outcomes by improving medication stewardship and informing which GMB-targeted therapies should be tested to improve patient outcomes.
PMID: 33635332
ISSN: 2473-9537
CID: 4795112

Non-Hodgkin Lymphoma with Synovial Involvement of the Knee

Kim, Brandon; Raphael, Bruce; Liu, Cynthia; Golden, Brian D
Musculoskeletal involvement occurs in approximately 25% of patients diagnosed with non-Hodgkin lymphoma (NHL). Skeletal involvement is typically secondary, with primary lymphoma of the bone being much rarer. We describe a case in which a 52-year-old man initially presented features suggestive of Lyme arthritis in his left knee. A synovial biopsy performed as part of a synovectomy procedure revealed a proliferative synovium with dense lymphoplasmacytic B cell infiltrate, suggestive of NHL. An inguinal lymph node biopsy was also performed but did not produce results pathologically similar to those of the left knee synovial biopsy.
PMID: 31785142
ISSN: 2328-5273
CID: 4249752

Leukemic mantle cell lymphoma and chronic lymphocytic leukemia: a rare composite lymphoma and literature review [Review]

Marks, Etan; Liu, Cynthia; Raphael, Bruce; Arbini, Arnaldo
Composite lymphomas are rare entities that either represent a collision of two separate lymphomas, or one lymphoma that expresses two distinct phenotypes. Mantle cell lymphoma has been reported in some composite lymphomas, but when combined with chronic lymphocytic leukemia, it can be difficult to recognize because of the phenotypic overlap of these two entities. We report a case of a 75-year-old male with a slowly progressing lymphocytosis, but who was otherwise asymptomatic. Flow cytometry revealed two different populations, one showing bright Lambda positivity and CD5(+), while the other was positive for both lambda and kappa and was CD5(+). Subsequently, cytogenetics revealed two different populations, one with a trisomy 12 and the other with a t(11;14). Additionally, immunohistochemistry on a bone marrow biopsy showed SOX-11 to be negative and cyclin D1 to be positive on scattered lymphocytes. This was consistent with a composite lymphoma of leukemic mantle cell lymphoma and chronic lymphocytic lymphoma.
ISSN: 1868-9256
CID: 3161812

A Rare Case of Composite Dural Extranodal Marginal Zone Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Bustoros, Mark; Liechty, Benjamin; Zagzag, David; Liu, Cynthia; Shepherd, Timothy; Gruber, Deborah; Raphael, Bruce; Placantonakis, Dimitris G
Background/UNASSIGNED:Primary extranodal marginal zone lymphoma (MZL) of the dura is a rare neoplastic entity in the central nervous system (CNS). Methods/UNASSIGNED:We used literature searches to identify previously reported cases of primary dural MZL. We also reviewed clinical, pathologic, and radiographic data of an adult patient with concurrent dural MZL and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Results/UNASSIGNED:We identified 104 cases of dural MZL in the literature. None of them presented concurrently with another type of non-Hodgkin lymphoma. This is the first report of composite lymphoma consisting of dural MZL and CLL/SLL in the bone marrow and lymph nodes. Conclusion/UNASSIGNED:Primary dural MZL is a rare, indolent low-grade CNS lymphoma, with a relatively good prognosis. Its treatment is multidisciplinary and often requires surgical intervention due to brain compression, along with low to moderate doses of radiotherapy and/or systemic chemotherapy.
PMID: 29740389
ISSN: 1664-2295
CID: 3085002

Hematological disorders

Chapter by: Raphael, Bruce G; Lin, Richard J
in: Medical aspects of disability for the rehabilitation professionals by Moroz, Alex; Flanagan, Steven R; Zaretsky, Herbert H [Eds]
[New York] : Springer Publishing Company, 2017
pp. ?-?
ISBN: 9780826133199
CID: 2558852

Hodgkin lymphoma patients demonstrate evidence of chronic activation/exhaustion in circulating T cell subsets [Meeting Abstract]

Diefenbach, Catherine S; Raphael, Bruce; Hymes, Kenneth; Grossbard, Michael; Moskovits, Tibor; Kaminetzky, David; Mcshea, Meghan; Martin, Peter; Ruan, Jia; Kozhaya, Lina; Bonakdar, Maryann; Abidoglu, Cem; Leonard, John; Unutmaz, Derya
ISSN: 1538-7445
CID: 2411312

Rapid and robust reversion to essential thrombocythemia on treatment with Decitabine in a case of hydroxyurea-induced t-MDS/AML

Horton, Joshua D; Arbini, Arnaldo A; Perle, Mary Ann; Raphael, Bruce G
Rapid remission of MDS/AML may be induced with Decitabine; however, significant megakaryocyte expansion and subsequent thrombocytosis may occur. Decitabine-mediated reversion of the MDS to benign ET via hypomethylation of JAK/STAT pathway repressors is one potential mechanism to explain this observed phenomenon.
PMID: 26783435
ISSN: 2050-0904
CID: 1921402

Circulating Memory T Cells Isolated from Hodgkin Lymphoma Patients Display Evidence of Exhaustion and Chronic Activation [Meeting Abstract]

Diefenbach, Catherine S; Raphael, Bruce G; Hymes, Kenneth B; Moskovits, Tibor; Kaminetzky, David; Martin, Peter; Ruan, Jia; Lauro, Stephanie; Banks, Danielle; Brown, Krysten; Bonakdar, Maryam; Abidoglu, Cem; Kozhaya, Lina; Leonard, John P; Unutmaz, Derya
ISSN: 1528-0020
CID: 1497562