scholarly journals Whole Genome Sequencing Reveals Recurrent Structural Driver Events in Peripheral T-Cell Lymphomas Not Otherwise Specified

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4115-4115
Author(s):  
Francesco Maura ◽  
Niccolò Bolli ◽  
Daniel Leongamornlert ◽  
Cristiana Carniti ◽  
Anna Dodero ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Advisory Board ◽  
The Other ◽  
Driver Mutations ◽  
Whole Genome ◽  
Advisory Committees ◽  
Not Otherwise Specified ◽  
T Cell Lymphomas ◽  
Peripheral T Cell Lymphomas

Abstract Historically, the differential diagnosis between different nodal peripheral T-cell lymphoma (PTCL) subtypes based on morphological and phenotypic grounds has posed great challenges. In the last few years, our knowledge of the molecular bases of different PTCLs has significantly expanded. However, peripheral T-cell lymphomas not otherwise specified (PTCL-NOSs) are still regarded to as a heterogeneous category encompassing PTCL cases not fitting other, more homogeneous, subtypes. In fact, PTCL-NOS is one of the few lymphoma subtypes where no recurrent driver mutations have been reported so far. In order to better characterized the PTCL-NOS genomic landscape, we decided to investigate 11 PTCL-NOS patients by a whole genome sequencing (WGS) approach (median coverage 27X). Ten out of eleven samples were collected from FFPE blocks and 2 were removed from analysis: one due to low cancer cell fraction (CCF) and the other based on cluster generation issues during sequencing likely caused by a hyper-fragmented DNA. Among the remaining 9 cases, we extracted 59,617 somatic base substitutions (range 2,471-10,756, median 6,358 per patient) and 20,531 small insertion-deletions (indels) (range 84-6,397, median 1,580). We were able to characterize the spectrum of FFPE-induced artefacts, mostly composed of point mutations and indels within LINE-1 (L1) elements, predominantly of the L1PA family. This is a crucial quality control step that could be applied to similar future studies from archive samples. Four samples were heavily involved by FFPE-related artefacts and were excluded for this reason. Using a non-negative matrix factorization (NNMF) algorithm we investigated for the first time the PTCL-NOS mutational signature landscape. We did not find novel processes in this entity, but rather known processes operative in other lymphoid malignancies. Among those: signatures 1 and 5, deriving from the age-related process of spontaneous deamination of methylated cytosines; signatures 2 and 13 deriving from aberrant activity of the APOBEC family of DNA deaminases; signatures 17 and 8, pertaining to two yet poorly characterized processes. The contribution of different processes to the mutational spectrum of each case was profoundly heterogeneous. Combining our data set with 64 previously published whole exome sequencing cases (23 ALCL, 15 AITLs, 9 PTCL-NOSs and 16 EATL-II), we confirmed the lack of recurrent driver mutations among PTCL-NOS. Taking advantage of WGS data, we therefore focused on structural variants (SVs: inversions, translocations, internal tandem duplications and deletions) and copy number alterations (CNAs). We found 372 SVs, with a stunning median of 73 per sample (range 56-86). Even more interesting, at least one complex event was observed in all but one patients, including one whole genome duplication (WGD) and five chromothripsis events in three patients, suggesting a critical role of SVs in shaping the PTCL-NOS genome. We found that known onco-drivers were recurrently disrupted by such events: the most frequent target was CDKN2A, deleted in 4 out of 5 patients, 2 of which carried homozygous deletions. Interestingly, PTEN loss was observed in 2 out of 4 CDKN2A-deleted patients. Given the high prevalence of these deletions, we extended our observation to an independent validation set of ALCLs (n=56), AITL (n=22) and PTCL-NOS (n=59) investigated by FISH (n=36), next generation sequencing (n=25) or SNP6 array series (n=76). Overall, CDKN2A was deleted in 22/59 (37%) PTCL-NOSs cases, and in 17/22 (77%) both alleles were lost. PTEN was deleted in 12/59 (20%) PTCL-NOS cases, all of which also carried a CDKN2A loss. Strikingly, the co-occurrence of CDKN2A and PTEN was found only among PTCL-NOS, and in none of the other entities. With the limitations of the small sample size, the presence of CDKN2A bi-allelic deletions was associated with inferior survival (25% [95% CI: 9-66%] 5-y OS for deleted cases vs 52% [95% CI: 28-96%] for wt/hemizygous cases, p=0.042) among patients treated with an autologous bone marrow transplant front line program for advance stage and high-risk disease (n=19). Our observations point at SVs as a main driver of PTCL-NOS, often involving known cancer genes and their downstream pathways. Furthermore, our data highlighted recurrent gene deletions that may be relevant for differential diagnosis within this category of lymphomas. Disclosures Bolli: Celgene: Honoraria. Chiappella:Roche: Other: lecture fees; Amgen: Other: lecture fees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Nanostring: Other: lecture fees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Teva: Other: lecture fees. Corradini:Celgene: Honoraria, Other: Advisory Board & Lecturer; Novartis: Honoraria, Other: Advisory Board & Lecturer; Roche: Honoraria, Other: Advisory Board & Lecturer; Sanofi: Honoraria, Other: Advisory Board & Lecturer; Gilead: Honoraria, Other: Advisory Board & Lecturer; Sandoz: Other: Advisory Board; Abbvie: Honoraria, Other: Advisory Board & Lecturer; Takeda: Honoraria, Other: Advisory Board & Lecturer; Amgen: Honoraria, Other: Advisory Board & Lecturer; Janssen: Honoraria, Other: Lecturer.

scholarly journals A Pilot Study Using Nivolumab in Combination with Standard of Care Chemotherapy in Newly Diagnosed Peripheral T-Cell Lymphomas

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2444-2444
Author(s):  
Brad Haverkos ◽  
Jasmine Zain ◽  
Manali Kamdar ◽  
Alexander Neuwelt ◽  
Steven M. Bair ◽  
...  
Keyword(s):  
T Cell ◽  
Pilot Study ◽  
Board Of Directors ◽  
Research Funding ◽  
Checkpoint Blockade ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
T Cell Lymphomas ◽  
Grade 3 ◽  
Peripheral T Cell Lymphomas

Abstract Introduction: The chemotherapy regimen dose adjusted (DA)-EPOCH (etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide) is a first line option for peripheral T-cell lymphomas (PTCLs), but for most subtypes relapses are common and long-term outcomes are poor. Checkpoint blockade is an immunotherapeutic approach that has shown efficacy as a single agent in relapsed PTCLs. The combination of checkpoint blockade and cytotoxic chemotherapy can have additive or synergistic activity by increasing the expression of neoantigens and overcoming mechanisms of resistance to immunotherapy such as weak tumor immunogenicity and an immune suppressive tumor microenvironment. Methods: We conducted a single arm, open-label clinical trial evaluating the efficacy and safety of the anti-PD1 antibody nivolumab (Nivo) in combination with DA-EPOCH in newly diagnosed PTCLs with ≥Stage II disease by Ann Arbor criteria. Pts were allowed to receive one cycle of chemotherapy prior to enrollment. Pts received Nivo (360 mg) followed by DA-EPOCH every 21 days for a planned six cycles unless treatment was stopped early for progression. For any immune related adverse event (irAE), Nivo was held until resolution to grade 1 and on ≤10mg prednisone. For serious grade 3-4 irAEs, Nivo was omitted with remaining DA-EPOCH cycles. DA-EPOCH was dose adjusted according to CALGB 50303 with the exception that pts could begin treatment at dose level -1 (i.e. 600 mg/m2 cyclophosphamide), at investigator's discretion. Pts who received one cycle of chemotherapy prior to enrollment received five cycles of Nivo + DA-EPOCH. After completing six cycles of chemotherapy, pts had the option to proceed with consolidative autologous stem cell transplant (ASCT) versus surveillance, according to patient/physician preference. Responses were assessed by PET/CT after 2 cycles of Nivo + DA-EPOCH and after the last cycle, using RECIL criteria. PFS events were defined as start of new treatment, progression, or death. Targeted next generation sequencing and multiplex immunohistochemistry of diagnostic tumor tissue are being performed. Results: We enrolled 18 pts: 4 angioimmunoblastic TCLs, 2 nodal PTCLs with T-follicular helper phenotype, 7 PTCL-NOS (not otherwise specified), 2 primary cutaneous gamma delta TCLs, 2 ALK negative anaplastic large cell lymphomas, and 1 subcutaneous panniculitis-like TCL who had progressed on methotrexate. Median age was 66 (range 43-77). International Prognostic Index (IPI) was high (4-5) in 50% (N=9), intermediate (2-3) in 33% (N=6), and low in 17% (N=3) of pts. Immune related AEs of all grades occurred in 78% (N=14) of pts and 39% (N=7) of pts experienced ≥grade 3 irAEs. 44% (N=8) of pts required discontinuation of Nivo due to irAEs. In the 8 pts whose irAEs resulted in discontinuation of Nivo, the irAE occurred prior to the second or third cycle of Nivo + DA-EPOCH. None of the 6 pts who received a cycle of anthracycline based chemotherapy prior to enrolling on trial experienced an irAE resulting in dose hold or discontinuation of Nivo, whereas 8 of 12 pts who did not receive a prior cycle of anthracycline based chemotherapy experienced an irAE requiring a dose hold or discontinuation of Nivo. The most common non-hematologic non-immune related ≥grade 2 AEs were related to infectious complications. Interim and end of induction overall response rates were 100% and 83%, respectively. We observed 10 CR, 5 PR, and 3 PD at the end of induction. There were 2 pts who received consolidation with ASCT. With a median follow up of 375 days (range 207-422), median modified PFS was 333 days (range 138-666) and median OS was not reached. The three pts with PD during induction were 2 PTCL-NOS (with a cytotoxic phenotype) and 1 AITL (with PD1+ tumor cells). Further correlative studies are ongoing to identify predictors of response. Discussion: In this pilot study using Nivo + DA-EPOCH for newly diagnosed PTCLs, we observed early immune related dose limiting AEs. Pts who received a cycle of anthracycline based chemotherapy prior to enrollment did not experience any dose limiting irAEs. We postulate that T-cell lymphoma pts are immunologically primed for irAEs, which can be mitigated by pre-treatment with chemotherapy. In a study in which half of pts were high risk by IPI, Nivo + DA-EPOCH led to encouraging high initial responses and lengthy responses in 2 PCGDTCL pts, thus warranting further investigation of this chemoimmunotherapeutic strategy. Figure 1 Figure 1. Disclosures Haverkos: Viracta Therapeutics: Consultancy. Zain: Secura Bio, DaichiSankyo, Abbvie: Research Funding; Secura Bio, Ono , Legend, Kiyowa Kirin, Myeloid Therapeutics Verastem Daichi Sankyo: Consultancy; Kiyoaw Kirin, Secura Bio, Seattle Genetics: Honoraria. Kamdar: KaryoPharm: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy; Celgene (BMS): Consultancy; Adaptive Biotechnologies: Consultancy; ADC Therapeutics: Consultancy; SeaGen: Speakers Bureau; Celgene: Other; AbbVie: Consultancy; TG Therapeutics: Research Funding; Genentech: Research Funding; Genetech: Other. Smith: Syros: Research Funding; Kura: Research Funding; Argenx: Research Funding. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.

scholarly journals Real Life Experience of Brentuximab Vedotin Plus CHP As First-Line Treatment in CD30 + Peripheral T-Cell Lymphomas

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4543-4543
Author(s):  
Domingo Domenech Eva ◽  
Juan-Manuel Sancho ◽  
Eva González-Barca ◽  
Nicholas Kelleher ◽  
Marta Rodriguez-Luaces ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Brentuximab Vedotin ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Variable Expression ◽  
T Cell Lymphomas ◽  
Peripheral T Cell Lymphomas

Abstract INTRODUCTION: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphomas classically treated with CHOP or CHOP-like regimens, with poor outcomes. CD30 is universally expressed and is pathognomonic in systemic anaplastic large cell lymphoma (sALCL), with variable expression among non-sALCL PTCL subtypes (40-60%). Recent data of frontline treatment with Brentuximab Vedotin (BV), an anti-CD30 monoclonal antibody, plus CHOP has demonstrated significant improvement in survival (ECHELON-2 clinical trial), becoming the new standard of care for sALCL in Europe. PATIENT AND METHODS: From February 2019 to April 2021, 21 patients with de novo newly diagnosed CD30+ PTCL have been treated with the combination of BV-CHP, in the centers of the Catalan Institute of Oncology in Spain. Survival curves were plotted by the Kaplan-Meier method. RESULTS: Clinical characteristics at diagnosis are shown in the table. Of interest, 5 of the 11 ALK negative ALCL patients were diagnosed of breast implant associated ALCL (BIA-ALCL) with extracapsular involvement. The number of cycles administrated were 108, with a median of 6 cycles per patient (range 1-6), all of them with G-CSF primary prophylaxis. At the time of this report, 1 patient was still on treatment and 2 patients without the final evaluation. Seven cycles (6%) were delayed (3 due to infection, 2 due to neutropenia grade 2, and 2 due to causes not related with chemotherapy).An adverse event was reported in 45 (44%) cycles, being the most frequent peripheral neuropathy in 14, nausea/vomiting in 9 and anemia in 8; all of them grade 1-2. Treatment was discontinued after 1 cycle in 1 patient due to progression. Of the 18 evaluable patients, the overall response rate (ORR) was of 83%, with 72% complete responses and 11% partial responses. Consolidative autologous stem cell transplant (ASCT) was performed in 5 patients. With a median follow-up of 14 months (limits: 1-24), 1-year progression-free survival (PFS) and overall survival (OS) was 68.2% (95% CI 44.6-91.7) and 82.2% (95% CI 63.9-100), respectively. CONCLUSIONS: Brentuximab Vedotin plus CHP is an effective regimen for CD30 positive PTCL, with a high rate of response. This combination presents a manageable safety profile, with the majority of patients completing the planned treatment. The incidence and severity of side effects are low, being peripheral neuropathy and neutropenia the most frequent. Figure 1 Figure 1. Disclosures Eva: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sancho: Roche, Janssen, Celgene-BMS, Gilead, Novartis, Takeda: Honoraria, Speakers Bureau; Roche, Janssen, Celgene-BMS, Gilead, Novartis, Incyte, Beigene: Speakers Bureau. González-Barca: Janssen: Consultancy, Honoraria, Other: Travel; EUSA Pharma: Consultancy, Honoraria; Kyowa Kirin: Consultancy; Roche: Honoraria, Other: Travel; Takeda. Abbvie: Honoraria. Ribera: ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau. Sureda: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Mundipharma: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Peripheral T-cell lymphomas, unspecified (or not otherwise specified): a review

2008 ◽  
Vol 26 (1) ◽  
pp. 8-20 ◽  
Author(s):  
Delvys Rodriguez-Abreu ◽  
Volmar Belisario Filho ◽  
Emanuele Zucca
Keyword(s):  
T Cell ◽  
Not Otherwise Specified ◽  
T Cell Lymphomas ◽  
Peripheral T Cell Lymphomas

scholarly journals Identification of Two CAR T-Cell Populations Associated with Complete Response or Progressive Disease in Adult Lymphoma Patients Treated with Axi-Cel

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 779-779 ◽  
Author(s):  
Zinaida Good ◽  
Jay Y. Spiegel ◽  
Bita Sahaf ◽  
Meena B. Malipatlolla ◽  
Matthew J. Frank ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Advisory Committees ◽  
Car T Cells ◽  
Scientific Advisory Board ◽  
Car T ◽  
Scientific Advisory

Axicabtagene ciloleucel (Axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). Long-term analysis of the ZUMA-1 phase 1-2 clinical trial showed that ~40% of Axi-cel patients remained progression-free at 2 years (Locke et al., Lancet Oncology 2019). Those patients who achieved a complete response (CR) at 6 months generally remained progression-free long-term. The biological basis for achieving a durable CR in patients receiving Axi-cel remains poorly understood. Here, we sought to identify CAR T-cell intrinsic features associated with CR at 6 months in DLBCL patients receiving commercial Axi-cel at our institution. Using mass cytometry, we assessed expression of 33 surface or intracellular proteins relevant to T-cell function on blood collected before CAR T cell infusion, on day 7 (peak expansion), and on day 21 (late expansion) post-infusion. To identify cell features that distinguish patients with durable CR (n = 11) from those who developed progressive disease (PD, n = 14) by 6 months following Axi-cel infusion, we performed differential abundance analysis of multiparametric protein expression on CAR T cells. This unsupervised analysis identified populations on day 7 associated with persistent CR or PD at 6 months. Using 10-fold cross-validation, we next fitted a least absolute shrinkage and selection operator (lasso) model that identified two clusters of CD4+ CAR T cells on day 7 as potentially predictive of clinical outcome. The first cluster identified by our model was associated with CR at 6 months and had high expression of CD45RO, CD57, PD1, and T-bet transcription factor. Analysis of protein co-expression in this cluster enabled us to define a simple gating scheme based on high expression of CD57 and T-bet, which captured a population of CD4+ CAR T cells on day 7 with greater expansion in patients experiencing a durable CR (mean±s.e.m. CR: 26.13%±2.59%, PD: 10.99%±2.53%, P = 0.0014). In contrast, the second cluster was associated with PD at 6 months and had high expression of CD25, TIGIT, and Helios transcription factor with no CD57. A CD57-negative Helios-positive gate captured a population of CD4+ CAR T cells was enriched on day 7 in patients who experienced progression (CR: 9.75%±2.70%, PD: 20.93%±3.70%, P = 0.016). Co-expression of CD4, CD25, and Helios on these CAR T cells highlights their similarity to regulatory T cells, which could provide a basis for their detrimental effects. In this exploratory analysis of 25 patients treated with Axi-cel, we identified two populations of CD4+ CAR T cells on day 7 that were highly associated with clinical outcome at 6 months. Ongoing analyses are underway to fully characterize this dataset, to explore the biological activity of the populations identified, and to assess the presence of other populations that may be associated with CAR-T expansion or neurotoxicity. This work demonstrates how multidimensional correlative studies can enhance our understanding of CAR T-cell biology and uncover populations associated with clinical outcome in CAR T cell therapies. This work was supported by the Parker Institute for Cancer Immunotherapy. Figure Disclosures Muffly: Pfizer: Consultancy; Adaptive: Research Funding; KITE: Consultancy. Miklos:Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees. Mackall:Vor: Other: Scientific Advisory Board; Roche: Other: Scientific Advisory Board; Adaptimmune LLC: Other: Scientific Advisory Board; Glaxo-Smith-Kline: Other: Scientific Advisory Board; Allogene: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Obsidian: Research Funding; Lyell: Consultancy, Equity Ownership, Other: Founder, Research Funding; Nektar: Other: Scientific Advisory Board; PACT: Other: Scientific Advisory Board; Bryologyx: Other: Scientific Advisory Board.

scholarly journals An overview of cutaneous T cell lymphomas

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 1882 ◽  
Author(s):  
Nooshin Bagherani ◽  
Bruce R. Smoller
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Mycosis Fungoides ◽  
Annual Incidence ◽  
Heterogeneous Group ◽  
Not Otherwise Specified ◽  
T Cell Lymphomas ◽  
Hodgkin's Lymphomas ◽  
Diagnosis Therapy ◽  
Peripheral T Cell Lymphomas

Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of extranodal non-Hodgkin’s lymphomas that are characterized by a cutaneous infiltration of malignant monoclonal T lymphocytes. They typically afflict adults with a median age of 55 to 60 years, and the annual incidence is about 0.5 per 100,000. Mycosis fungoides, Sézary syndrome, and primary cutaneous peripheral T cell lymphomas not otherwise specified are the most important subtypes of CTCL. CTCL is a complicated concept in terms of etiopathogenesis, diagnosis, therapy, and prognosis. Herein, we summarize advances which have been achieved in these fields.

High Risk Multiple Myeloma Demonstrates Marked Spatial Genomic Heterogeneity Between Focal Lesions and Random Bone Marrow; Implications for Targeted Therapy and Treatment Resistance

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 20-20 ◽  
Author(s):  
Niels Weinhold ◽  
Shweta S. Chavan ◽  
Christoph Heuck ◽  
Owen W Stephens ◽  
Ruslana Tytarenko ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Driver Mutations ◽  
University Of Arkansas ◽  
Medical Sciences ◽  
Clonal Heterogeneity ◽  
Advisory Committees ◽  
Site Specific

Abstract Introduction: Recent next generation sequencing studies have defined the mutation spectrum in multiple myeloma (MM) and uncovered significant intra-clonal heterogeneity, showing that clinically relevant mutations are often only present in sub-clones. Longitudinal analyses demonstrated that tumor clones under therapeutic pressure behave in a "Darwinian" fashion, with shifting dominance of tumor clones over time. Recently, stratification of clonal substructures in distinct areas of the tumor bulk has been shown for multiple cancer types. So far, spatial genomic heterogeneity has not been systematically analyzed in MM. This stratification in space is becoming increasingly important as we begin to understand the contribution of Focal Lesions (FL) to tumor progression and emergence of drug resistance in MM. We have recently shown that high numbers of FL are associated with gene expression profiling (GEP) defined high risk (HR). A comparison of GEP data of 170 paired random bone marrow (RBM) and FL aspirates showed differences in risk signatures, supporting the concept of spatial clonal heterogeneity. In this study we have extended the analysis by performing whole exome sequencing (WES) and genotyping on paired RBM and FL in order to gain further insight into spatial clonal heterogeneity in MM and to find site-specific single nucleotide variant (SNV) spectra and copy number alterations (CNA), which contribute to disease progression and could form the basis of adaptation of the tumor to therapeutic pressure. Materials and Methods: We included 50 Total Therapy MM patients for whom paired CD138-enriched RBMA and FL samples were available. Leukapheresis products were used as controls. For WES we applied the Agilent qXT kit and a modified Agilent SureSelect Clinical Research Exome bait design additionally covering the immunoglobulin heavy chain locus and sequences located within 1Mb of the MYC locus. Paired-End sequencing to a minimum average coverage of 120x was performed on an Illumina HiSeq 2500. Sequencing data were aligned to the Ensembl GRCh37/hg19 human reference using BWA. Somatic variants were identified using MuTect. For detection of CNA we analyzed Illumina HumanOmni 2.5 bead chip data with GenomeStudio. Subclonal reconstruction was performed using PhyloWGS. Mutational signatures were investigated using SomaticSignatures. The GEP70 risk signature was calculated as described previously. Informed consent in accordance with the Declaration of Helsinki was obtained for all cases included in this study. Results: Analyzing RBM and FL WES data, we detected between 100 and 200 somatic SNVs in covered regions, with approximately 30% of them being non-synonymous, and less than 5% stop gained or splice site variants. A comparison of paired RBM and FL WES data showed different extents of spatial heterogeneity. Some pairs had very similar mutation profiles with up to 90% shared variants, whereas others demonstrated marked heterogeneity of point mutations. We did not detect differences in mutational signatures between RBM and FL using the 'SomaticSignatures' package. We found site-specific driver mutations with high variant allele frequencies, indicating replacement of other clones in these areas. For example we observed a clonal KRAS mutation exclusively in the RBM, whereas a NRAS variant was only identified in the paired FL. The same holds true for large-scale CNAs (>1 Mb). We identified a case in which the high risk CNAs gain(1q) and del(17p) were only detectable in the FL. Further examples for site-specific CNAs were a del(10q21) and a gain(4q13) detected in FLs only. As a prominent pattern, we observed outgrowth of sub-clonal RBM CNAs as clonal events in the FL. Based on mutation and CNA data we identified different forms of spatial evolution, including parallel, linear and branching patterns. Of note, a stratified analysis by GEP70-defined risk showed that a more pronounced spatial genomic heterogeneity of SNVs and CNAs was associated with HR disease. Conclusion: We show that spatial heterogeneity in clonal substructure exists in MM and that it is more pronounced in HR. The existence of site-specific HR CNAs and driver mutations highlights the importance of heterogeneity analyses for targeted treatment strategies, thereby facilitating optimal personalized MM medicine. Disclosures Weinhold: University of Arkansas for Medical Sciences: Employment; Janssen Cilag: Other: Advisory Board. Chavan:University of Arkansas for Medical Sciences: Employment. Heuck:Millenium: Other: Advisory Board; Janssen: Other: Advisory Board; Celgene: Consultancy; University of Arkansas for Medical Sciences: Employment; Foundation Medicine: Honoraria. Stephens:University of Arkansas for Medical Sciences: Employment. Tytarenko:University of Arkansas for Medical Sciences: Employment. Bauer:University of Arkansas for Medical Sciences: Employment. Peterson:University of Arkansas for Medical Sciences: Employment. Ashby:University of Arkansas for Medical Sciences: Employment. Stein:University of Arkansas for Medical Sciences: Employment. Johann:University of Arkansas for Medical Sciences: Employment. Johnson:University of Arkansas for Medical Sciences: Employment. Yaccoby:University of Arkansas for Medical Sciences: Employment. Epstein:University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Zangari:Novartis: Research Funding; Onyx: Research Funding; Millennium: Research Funding; University of Arkansas for Medical Sciences: Employment. Schinke:University of Arkansas for Medical Sciences: Employment. Thanendrarajan:University of Arkansas for Medical Sciences: Employment. Davies:Millenium: Consultancy; Onyx: Consultancy; Celgene: Consultancy; University of Arkansas for Medical Sciences: Employment; Janssen: Consultancy. Barlogie:University of Arkansas for Medical Sciences: Employment. Morgan:University of Arkansas for Medical Sciences: Employment; MMRF: Honoraria; CancerNet: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Weismann Institute: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters

Blood ◽  
2012 ◽  
Vol 120 (7) ◽  
pp. 1466-1469 ◽  
Author(s):  
François Lemonnier ◽  
Lucile Couronné ◽  
Marie Parrens ◽  
Jean-Philippe Jaïs ◽  
Marion Travert ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
T Cell Lymphoma ◽  
Not Otherwise Specified ◽  
T Cell Lymphomas ◽  
Stage Disease ◽  
Peripheral T Cell Lymphomas

Abstract Inactivating mutations of the Ten-Eleven Translocation 2 (TET2) gene were first identified in myeloid malignancies and more recently in peripheral T-cell lymphomas (PTCLs). In the present study, we investigated the presence of TET2 coding sequence mutations and their clinical relevance in a large cohort of 190 PTCL patients. TET2 mutations were identified in 40 of 86 (47%) cases of angioimmunoblastic T-cell lymphoma (AITL) and in 22 of 58 (38%) cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), but were absent in all other PTCL entities, with the exception of 2 of 10 cases of enteropathy-associated T-cell lymphoma. Among PTCL-NOS, a heterogeneous group of lymphoma-comprising cases likely to derive from Th follicular (TFH) cells similarly to AITL, TET2 mutations were more frequent when PTCL-NOS expressed TFH markers and/or had features reminiscent of AITL (58% vs 24%, P = .01). In the AITL and PTCL-NOS subgroups, TET2 mutations were associated with advanced-stage disease, thrombocytopenia, high International Prognostic Index scores, and a shorter progression-free survival.

scholarly journals Biology of peripheral T cell lymphomas – Not otherwise specified: Is something finally happening?

Pathogenesis ◽  
2016 ◽  
Vol 3 (1) ◽  
pp. 9-18 ◽  
Author(s):  
Francesco Maura ◽  
Anna Dodero ◽  
Cristiana Carniti ◽  
Niccolò Bolli
Keyword(s):  
T Cell ◽  
Not Otherwise Specified ◽  
T Cell Lymphomas ◽  
Peripheral T Cell Lymphomas
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