Recurrent VAV1 Abnormalities in Angioimmunoblastic T Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4104-4104
Author(s):  
Daisuke Komori ◽  
Mamiko Sakata-Yanagimoto ◽  
Sharna Tanzima Nuhat ◽  
Kota Fukumoto ◽  
Manabu Fujisawa ◽  
...  
Keyword(s):  
T Cell ◽  
Rna Sequencing ◽  
Clinical Features ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Jurkat Cells ◽  
Nih3t3 Cells ◽  
Angioimmunoblastic T Cell Lymphoma ◽  
Disease Specific

Abstract Background: Angioimmunoblastic T cell lymphoma (AITL) is a subset of peripheral T cell lymphomas (PTCLs). AITL has very specific clinical features, including high fever, skin rush, and autoimmune-like manifestations. The molecular pathogenesis of AITL is poorly understood despite the recent progress in genetics of this disease. We and others previously identified disease specific ras homolog family member A (RHOA) mutations together with muations in epigenetic regulators, tet methylcytosine dioxygenase 2 (TET2) and DNA methyltransferase 3 alpha (DNMT3A) mutations, and isocitrate dehydrogenase (NADP(+)) 2, mitochondrial (IDH2) in AITL. Thesemutations were also frequent in PTCL, not otherwise specified (PTCL-NOS) having features of AITL. RHOA, a small GTPase is predominantly activated by guanine nucleotide exchange factors (GEFs). VAV1encodes a GEF, serving as an important mediator of T-cell receptor signaling pathway. Phosphorylation of VAV1 occurs within seconds in response to antigen stimulation of the T-cell receptors by Syk and Src-family tyrosine kinases and initiate downstream signaling. Objective: We aim to identify novel disease specific gene mutations in AITL besides RHOA. Methods: We performed RNA sequencing of 9 PTCL samples, including 6 AITL and 3 PTCL-NOS. Targeted deep sequencing of VAV1 was performed for 139 PTCL samples, including 93 AITL and 46 PTCL-NOS, 48 of which have RHOAmutations. VAV1 wild-type (WT), VAV1-STAP2, and VAV1 mutant (p.173_177del, p.165_174del, and p.Pro615Leu) cDNA was subcloned into pEF vector. Nuclear factor of activated T cell (NFAT) activity in response to CD3 stimulation was examined in Jurkat cells transiently transfected with a reporter vector containing NFAT response element (NFAT-RE) together with VAV1 WT and mutant cDNAs. The levels of interleukin-2 (IL-2) in response to CD3 stimulation were examined for the supernatant of Jurkat cells inducibly expressing VAV1 WT or VAV1-STAP2 cDNAs. Rac1 activation was examined in NIH3T3 cells transiently transfected with VAV1WT and mutant cDNAs. Results: RNA sequencing identified a fusion gene involving VAV1 and STAP2 in an AITL sample without RHOA mutations. Moreover, targeted sequencing of VAV1 identified 2 in-flame deletion mutations in an acidic region (c.C518_529del:p.173_177del and c.C494_520del:p.165_174del) in AITL samples and 2 missense mutations in a zinc finger and SH3-SH2-SH3 module (c.G1668C:p.Glu556Asp and c.C1844T:p.Pro615Leu) in PTCL-NOS and AITL samples, respectively. All of these VAV1 mutations were found in the samples without RHOA mutations. The phosphorylation of VAV1 at Tyr 174 was enhanced in Jurkat cells expressing VAV1-STAP2 cDNA than those with VAV1 WT cDNA or mock. The phosphorylation was efficiently blocked by Src inhibitors, PP2 and dasatinib. Transient transduction of VAV1-STAP2, VAV1 p.173_177del, p.165_174del, and p.Pro615Leu cDNA in Jurkat cells resulted in enhanced NFAT activity. Moreover, the aberrant reporter activity was blocked by Src-family kinase inhibitors. Jurkat cells inducibly expressing VAV1-STAP2 cDNA showed higher IL-2 secretion than those with mock or VAV1 WT. RAC1 activation was higher in NIH3T3 cells transfected with VAV1 p.173_177del and p.165_174del mutant cDNA than those with VAV1 p.Pro615Leu mutant and VAV1-STAP2 cDNA. Conclusions: Recurrent VAV1 abnormalities were found in AITL and PTCL-NOS samples. Our data suggest that the VAV1 mutations may contribute to its clinical features and the VAV1 mutants can be a new therapeutic target. Disclosures Izutsu: Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Mundipharma KK: Research Funding. Ogawa:Takeda Pharmaceuticals: Consultancy, Research Funding; Kan research institute: Consultancy, Research Funding; Sumitomo Dainippon Pharma: Research Funding.

scholarly journals Results of Intercontinental Cooperative Non-Hodgkin T-Cell Lymphoma Prospective Registry Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4035-4035
Author(s):  
Sang Eun Yoon ◽  
Seok Jin Kim ◽  
Tsai-Yun Chen ◽  
Yong Park ◽  
Li Mei Poon ◽  
...  
Keyword(s):  
T Cell ◽  
Treatment Outcomes ◽  
Clinical Features ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Registry Study ◽  
Asian Countries ◽  
T Cell Lymphomas ◽  
Number Of Patients

Introduction T-cell lymphoma is a group of heterogeneous diseases with various clinical behaviors and treatment outcomes, representing 10-15% of non-Hodgkin lymphomas. Owing to its rarity and heterogeneity, the standard treatment approach for T-cell lymphoma is still not established. Accordingly, conventional chemotherapy regimens adapted from B-cell lymphoma treatment has been used for T-cell lymphoma. However, their outcome is still not satisfactory, and there are limited data representing the real-world situation in terms of clinical features and treatment outcomes. Given the incidence of T-cell lymphoma is relatively higher in Asian than Western countries; a comprehensive registry study focusing on Asian patients with T-cell lymphoma could be helpful for better understanding of T-cell lymphoma as well as the development of more effective treatment strategy. Methods We performed a multi-national, multi-center, prospective registry study for patients with T-cell lymphoma and enrolled patients between 01-March-2016 and 31-January-2019. All patients received chemotherapy with curative intent after diagnosis, and were pathologically diagnosed with T-cell lymphoma according to the 2008 World Health Organization classification of lymphoid neoplasms. Patients belonged to any one of following clinical situations could be enrolled: (1) newly diagnosed, treatment-naïve patients; (2) patients who started treatment or completed treatment; (3) relapsed or refractory patients. After we enrolled the planned number of patients (n = 500), we analyzed clinical features and treatment outcomes. Results Out of 500 patients enrolled from nine Asian countries (Korea, China, Taiwan, Singapore, Indonesia, Bangladeshi, Vietnam, Malaysia, and Philippines), 490 patients were analyzed because 10 patients with insufficient information were excluded. The median age was 59 years (range, 20-85), male patients (59%) were predominant compared to female patients (41%). Extranodal NK/T-cell lymphoma (ENKTL) was the most common (28%) and angioimmunoblastic T-cell lymphoma (AITL) was the second common (24%). Peripheral T-cell lymphoma, not-otherwise specified (PTCL-NOS, 20%) and ALK+/- anaplastic large cell lymphoma (ALCL, 16%) were also major subtypes of T-cell lymphoma. The proportion of stage IV was 40%, however, the distribution of stage was different between ENKTL and nodal T-cell lymphomas such as PTCL-NOS. The CHOP (Cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens accounted for the mainstay of primary treatment for nodal T-cell lymphoma whereas non-anthracycline-based chemotherapy regimens such as SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide) and GemOx-L (gemcitabine, oxaliplatin, and L-asparagainase) were mainly used for ENKTL. The overall survival of ENKTL was not significantly different from that of PTCL-NOS, AITL and ALK+/- ALCL. Conclusions Our study showed the distribution of T-cell lymphoma subtypes and tumor burdens at the time of diagnosis in Asian countries. Although clinical features of ENKTL are different from that of nodal T-cell lymphomas consisting of PTCL-NOS, AITL and ALK+/- ALCL, and the different types of treatment were used, survival outcome of patients were not significantly different. This finding might be associated with improved treatment outcomes of ENKTL compared to the past. However, considering a substantial number of patients experienced treatment failure in patients with PTCL-NOS as well as ENKTL, more effective treatment strategy should be warranted. Figure Disclosures Kim: F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding.

Clinical features, outcome and prognostic factors of 87 patients with angioimmunoblastic T cell lymphoma in Taiwan

2016 ◽  
Vol 104 (2) ◽  
pp. 256-265 ◽  
Author(s):  
Hsiao-Wen Kao ◽  
Tung-Liang Lin ◽  
Lee-Yung Shih ◽  
Po Dunn ◽  
Ming-Chung Kuo ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
T Cell ◽  
Clinical Features ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Angioimmunoblastic T Cell Lymphoma

scholarly journals VAV1 Mutations Contributes to the Development of T-Cell Malignancies in Mice

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 300-300
Author(s):  
Kota Fukumoto ◽  
Mamiko Sakata-Yanagimoto ◽  
Manabu Fujisawa ◽  
Tatsuhiro Sakamoto ◽  
Tran B. Nguyen ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Suspension ◽  
Tumor Cells ◽  
Rna Sequencing ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Equity Ownership ◽  
T Cell Malignancies

Background: VAV1 is known as an important mediator of T-cell receptor (TCR) signaling through its guanine exchange factor (GEF)-dependent and independent functions. Recent studies identified activating VAV1 mutations in several types of T-cell malignancies including peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-negative anaplastic large cell lymphoma (ALCL), and adult T-cell lymphoma/leukemia (ATLL). However, the functions of VAV1 mutations in T-cell malignancies have not been clarified. Objective: We aim to identify the oncogenic signaling of VAV1 mutations in T cells using genetically engineered mice. Methods: Human VAV1 mutant (p.165_174del) (VAV1-Del) and VAV1-STAP2 fusion cDNAs, identified in our PTCL cohort (Fujisawa, Leukemia 2018) were cloned into a VA vector under the CD2 promoter. The vectors were injected into eggs to generate VAV1-Del and VAV1-STAP2 transgenic mice. The mice were further crossed with p53-/- mice to generate p53-/- x VAV1-Del or p53-/- x VAV1-STAP2 mice. Cell surface markers of tumor cells were analyzed by flowcytometry. Cell suspension of tumors were cultured, and were intraperitoneally injected into BALBc/nu mice to examine the cell-autonomous proliferative activity in vitro and tumor-initiating capacity in vivo, respectively. RNA sequencing was performed to clarify the downstream signaling of VAV1 mutations. Results: The p53-/- mice expressing VAV1 mutants showed significantly poorer overall survival (OS) compared to p53-/- mice (p53-/- x VAV1-Del, median 16.6 weeks; p53-/- x VAV1-STAP2, median 18.6 weeks; vs p53-/-, median 33.7 weeks: p<0.001), while mice with VAV1 expression in the wild-type (WT) background as well as WT mice remained alive during the observation period (>50 weeks). p53-/- x VAV1-Del and p53-/- x VAV1-STAP2 mice developed either T-cell lymphoblastic leukemias (LBL) infiltrating into thymus, lung, spleen, and liver, or mature T-cell lymphomas (Lym) into lymph nodes, spleen, and liver. In contrast, p53-/- mice developed only T-LBL at thymus. Flow cytometric analysis showed that most of T-LBL cells developed in p53-/- mice with VAV1 mutants were CD8+ single positive (SP), while those in p53-/- mice were either CD4+CD8+ (double positive, DP) or CD8+ SP. Lym cells in p53-/- mice with VAV1 mutants were either CD4+ SP or CD4-CD8- (double negative, DN) (in p53-/- x VAV1-Del mice, 5/9 CD8+ SP T-LBL, 1/9 DP T-LBL , 2/9 CD4+ SP Lym , and 1/9 DN Lym; in p53-/- x VAV1-STAP2 mice, 9/13 CD8+ SP T-LBL, 1/13 CD4+ SP Lym , and 3/13 DN Lym; p53-/- mice, 3/7 CD8+ SP T-LBL and 4/7 DP T-LBL). T-LBL with or without VAV1 mutants were immortalized in vitro over 4 weeks without any cytokines, while Lym with VAV1 mutations could not be maintained in vitro. The BALBc/nu mice transplanted with cell suspension of either T-LBL or Lym with VAV1 mutants were succumbed to death around 10 or 15 weeks, respectively. All the tumor cells developed in transplanted mice showed the similar immunophenotype to those of donor cells. Gene set enrichment analysis (GSEA) following RNA sequencing showed that G2M check point, E2F targets, mitotic spindle, PI3K/Akt/mTOR signaling, and hedgehog signaling were enriched in CD8+ SP T-LBL with VAV1 mutants compared with DP T-LBL in p53-/- mice, while E2F targets, MYC targets, G2M checkpoint, Oxidative phosphorylation, and MTORC1 signaling were upregulated in CD4+ SP Lym with VAV1 mutants in comparison with WT CD4+ spleen cells. We previously reported that TCR and Tfh pathways were enriched in TET2-/-/RHOA G17V mice through activation of VAV1 (Tran, ASH 2018). Curiously, neither of them were enriched in CD4+ SP Lym with VAV1 mutants, while TCR pathway was enriched in T-LBL with VAV1 mutants. Cell viability assay using panels over 1400 drugs showed that PI3K/Akt/mTOR pathway inhibitors and cell-cycle inhibitors effectively suppressed the cell growth of T-LBL with VAV1 mutants in vitro. Conclusions: Expression of VAV1 mutants promoted the development of T-cell malignancies in mice. Our mouse models may provide the efficient tools to screen new therapeutic targets in T-cell malignancies with VAV1 mutations. Disclosures Ohshima: NEC Corp.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Celgene Corp.: Honoraria, Research Funding; SRL, Inc.: Consultancy. Ogawa:Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; RegCell Corporation: Equity Ownership; Asahi Genomics: Equity Ownership; Qiagen Corporation: Patents & Royalties; Kan Research Laboratory, Inc.: Consultancy; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership.

A Targeted Mutational Landscape of Angioimmunoblastic T-Cell Lymphoma: Association Between Advanced Age and Mutations in TET2 and DNMT3A

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 299-299
Author(s):  
Oliver Weigert ◽  
Nadja Kopp ◽  
Sudha Bolla ◽  
Oreofe Odejide ◽  
Dan Toscano ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Angioimmunoblastic T Cell Lymphoma ◽  
Number Of Genes ◽  
Tet2 Mutation

Abstract Abstract 299 Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of T-cell lymphoma that manifests with a broad array of neoplastic and paraneoplastic manifestations, including generalized lymphadenopathy, hepatosplenomegaly, systemic symptoms, rash and hypergammaglobulinemia. AITL accounts for approximately 20% of T-cell lymphomas and 1–2% of all non-Hodgkin lymphomas (NHL). Median survival among patients with AITL is less than 3 years, although the course of illness varies widely. Histologic examination of AITL characteristically demonstrates proliferation of high endothelial venules and a polymorphic infiltrate, malignant cells that resemble CD4+ follicular helper T-cells and occasional EBV-positive lymphoid cells. The genetics of AITL remain almost completely undefined, in part because of the low tumor cell fraction and the abundance of non-malignant bystander cells. We reasoned that targeted sequencing of selected genes of interest would increase coverage and thereby enable the detection of low frequency variants present with malignant AITL cells. To define a targeted mutational landscape of AITL, we performed exon capture and next-generation sequencing of all coding exons of 197 genes known to be recurrently altered in cases of NHL. Single nucleotide variants (SNVs) and insertions/deletions were confirmed by manual review of sequencing reads and a subset was validated by Sanger sequencing of tumor and germline tissue. Twenty-six cases collected from three sites in the USA had adequate tumor specimens available and resulted in high-quality reads (median depth of coverage∼300). Median age among the 26 cases was 66.5 years (range 30–89). Twelve (46%) patients were male. Among 21 cases with adequate clinical annotation, all 21 had advanced stage disease (11 stage 3, 10 stage 4), 13 (62%) had B-symptoms and 19 (90%) had an ECOG performance score of 0–2. Ten patients received CHOP-like regimens, 4 received non-anthracycline containing chemotherapy regimens, 5 received prednisone monotherapy, 2 received cyclosporine monotherapy, and one patient underwent allogeneic stem cell transplantation after cytoreduction with alemtuzumab. Among the 17 patients with staging after first-line treatment, 8 (47%) achieved a complete response, 3 (18%) achieved a partial response, 1 (6%) had stable disease and 5 (29%) had progression of disease. Median overall survival among the 26 patients was 420 days with a median follow-up of 426 days (range 21–3532). Recent studies have identified both TET2 and DNMT3A mutations in a small number of AITL samples as well as hematopoietic stem cells from the same patients. From the 26 cases, we identified 28 TET2 mutations (13 frameshift, 8 nonsense, 5 missense, 2 splice site) in 17 (65.4%) cases, including 5 cases with 2 TET2 mutations and 2 cases with 3 TET2 mutations. Among the latter, the fractions of mutant reads suggested that one mutation was present within all tumor cells and the other 2 mutations were present in subclones. Six of 17 cases with TET2 mutations also harbored mutations in DNMT3A, compared with 0 of 9 cases that lacked TET2 mutations (p=0.06). Median age for patients with wild-type TET2 was 56 years (range 30–83), 68 years for patients with one TET2 mutation (range 55–89), and 77 years for patients with 2 or 3 TET2 mutations (range 59–84; p<10−4). Median age for patients with wild-type DNMT3A was 64 years (range 30–84) and 75.5 years for patients with mutated DNMT3A (range 64–89; p=0.03). Known gain-of-function mutations were identified at JAK3 V722I (n=2) and IDH2 R172K (n=1). Frame-shift mutations were recovered in ABCA7 (n=1), ARID1B (n=1), CREBBP (n=2), GNAS (n=1), IKZF2 (n=2), PRDM1 (n=2), SMARCA2 (n=1), and TNFRSF14 (n=1). Nonsense mutations were recovered in ALPK2 (n=1), CCND3 (n=2), and CHD8 (n=2). Only 2 cases harbored TP53 mutations (M133R, S261_splice). Additional missense variants were identified across a large number of genes, including several previously described in the COSMIC database. In conclusion, the genetics of AITL vary broadly across cases, with a small number of genes previously associated with NHL harboring recurrent mutations. Mutations of DNMT3A commonly occur in combination with one or more mutations in TET2. Mutation of either locus is associated with advanced age, supporting the hypothesis that the mutations are acquired over time within hematopoietic stem cells. Disclosures: Horwitz: Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding. Weinstock:Novartis: Consultancy, Research Funding.

scholarly journals Clinical Features and Treatment Outcomes of Angioimmunoblastic T-Cell Lymphoma: An Analysis from a Nationwide Multicenter Registry, Thailand

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5064-5064
Author(s):  
Chittima Sirijerachai ◽  
Kanchana Chansung ◽  
Arnuparp Lekhakula ◽  
Jakrawadee Julamanee ◽  
Kitsada Wudhikarn ◽  
...  
Keyword(s):  
T Cell ◽  
Complete Remission ◽  
Treatment Outcomes ◽  
Clinical Features ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Disease Stage ◽  
Peripheral T Cell Lymphoma ◽  
Angioimmunoblastic T Cell Lymphoma ◽  
Multicenter Registry

Abstract OBJECTIVES: To analyze clinical features, treatment outcomes in Thai patients with angioimmunoblastic T cell lymphoma (AITL). PATIENTS AND METHODS: From a nationwide multicenter registry of 4,056 NHL patients in Thailand between 2007 and 2014, there were a total of 54 angioimmunoblastic T cell lymphoma (AITL) patients. The clinical features and treatment outcomes were analyzed. RESULTS: There were a total of 54 cases accounted to the prevalence of 1.2 % of NHL and 12% of peripheral T cell lymphoma. The median age was 59 years (range 35-81). Male: female was 1.5:1. Seventy-eight percent of patients had advanced disease (stage III, IV), 69% had B symptoms, 28% had poor performance status (ECOG > 2) and 61% had elevated serum LDH level. Extranodal involvement was 56 %; the most common sites of which were bone marrow (30%) and liver (19 %). Thirty-five percent of the patients had IPI score > 2 and 7% had PIT >2. Eighty-one percent of patients were treated with chemotherapy of which CHOP/CHOP-like was the main regimen. Of the 43 evaluable patients receiving chemotherapy, complete remission was achieved in 41.9%. Forty-four percent of patients with complete remission had disease progression. With the median follow-up time of 65 months, the 5-year overall survival was comparable to peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), (28% vs. 37%, p=0.7). On multivariate analysis, response to treatment (at least PR) was associated with better outcome (HR 0.13, 95%CI 0.05-0.33, p= 0.000). Patients with PIT > 2 or B symptoms trended to have inferior survival outcome, although statistical significant was not achieve (HR 3.2, 95%CI 0.36-27.95, p=0.3; HR 2.3, 95%CI 0.78-7.31, p=0.13). CONCLUSIONS: The prevalence of Thai patients with AITL was much less than data reported from the international T-cell lymphoma project (18% of T-NHLs) (Vose et al, JCO2008;26:4124-30). The long-term survival was not inferior to patients with PTCL, NOS. Disclosures Khuhapinant: Roche: Honoraria.

Clinical features and treatment outcomes of angioimmunoblastic T-cell lymphoma

2007 ◽  
Vol 48 (4) ◽  
pp. 716-722 ◽  
Author(s):  
Byeong-Bae Park ◽  
Baek-Yeol Ryoo ◽  
Jae H. Lee ◽  
Hyuck Kwon ◽  
Sung H. Yang ◽  
...  
Keyword(s):  
T Cell ◽  
Treatment Outcomes ◽  
Clinical Features ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Angioimmunoblastic T Cell Lymphoma

Duvelisib (IPI-145), a Phosphoinositide-3-Kinase-δ,γ Inhibitor, Shows Activity in Patients with Relapsed/Refractory T-Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 803-803 ◽  
Author(s):  
Steven M. Horwitz ◽  
Pierluigi Porcu ◽  
Ian Flinn ◽  
Brad S. Kahl ◽  
Jennifer Sweeney ◽  
...  
Keyword(s):  
T Cell ◽  
Median Time ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
T Cell Lymphoma ◽  
Cutaneous Lymphoma ◽  
Clinical Activity ◽  
Disease Specific

Abstract Introduction: Peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) are uncommon lymphoid malignancies. Approved agents in the relapsed setting have overall response rates (ORR) in the range of 25-35%. Phosphoinositide-3-Kinases (PI3K) are pivotal in cell signaling and regulate multiple cellular functions relevant to oncogenesis. PI3K-δ and PI3K-γ isoforms are preferentially expressed in leukocytes with distinct roles in T-cell function. PI3K-δ and PI3K-γ are central to the growth and survival of certain T-cell malignancies and inhibition of PI3K is a therapeutic strategy for PTCL and CTCL. Duvelisib (IPI-145), an oral inhibitor of PI3K-δ and PI3K-γ, was studied in a phase 1 trial in hematologic malignancies with disease-specific expansion cohorts at the maximum tolerated dose (MTD). Responses were seen in a substantial number of patients with relapsed or refractory PTCL and CTCL. Methods: This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of duvelisib administered twice daily (BID), continuously in 28-day cycles. Patients with relapsed or refractory leukemia or lymphoma received doses ranging from 8 mg to 100 mg BID. A disease-specific cohort at the MTD included PTCL and CTCL patients. The pharmacodynamics of duvelisib were assessed by early positron-emission tomography (PET) in a subset of patients and in serum through evaluation of a panel of cytokines, chemokines, and matrix metalloproteinase. Results: Thirty-three patients with TCL (17 CTCL, 16 PTCL) received duvelisib primarily at the MTD of 75 mg BID (25 mg, n=1; 50 mg, n=1; 60 mg, n=4; 75 mg, n=25; 100 mg, n=2). The median age was 64 years (range: 34-86), and the median number of prior therapies was 4 (range: 1-11). The median time from last prior therapy to first dose of duvelisib was 1.05 months (range: 0.2-36). Thirty-one patients were evaluable for efficacy, with an ORR of 42% (13/31). The ORR in PTCL was 47% (7/15, 2 complete responses [CR], 5 partial responses [PR]) and in CTCL 38% (6/16, 6 PR). The median time to response was 1.9 months (range: 1.5-3.8). Median overall survival (OS) was 36.4 weeks (95% CI: 18.6, –) for patients with PTCL. The median OS was not yet reached for patients with CTCL. The median number of treatment cycles was 3.1 (range: 0.5-12.5), with 14 (42%) on treatment ≥4 cycles (16 weeks). Pharmacodynamic results showed that within 8 days of starting treatment with duvelisib, modulation of serum cytokines and chemokines known to play a role in leukocyte migration and support the tumor microenvironment was observed. Furthermore, a reduction in standard uptake value (SUV) from baseline was observed in 6/11 patients evaluated by PET at Cycle 1 Day 22. (All 6 patients with reduction in SUV received duvelisib ≥60 mg BID). Twenty-six (79%) patients had adverse events (AEs) ≥Grade 3, with the most common (≥10%) being increased ALT/AST (n=12, 36%), rash (combined terms) (n=7, 21%), and neutropenia (n=5, 15%). Ten (30%) patients discontinued treatment due to an AE, with the most common (>1 patient) being increased ALT/AST [n=5 (4 CTCL, 1 PTCL), 15%]. Three TCL patients died on treatment or within 30 days of the last dose of duvelisib, one due to disease progression, one who declined supportive therapy, and one due to HSV pneumonia (patient was not receiving HSV prophylaxis). Conclusions: Duvelisib has shown clinical activity in patients with relapsed/refractory TCL (ORR 42%, including 2 CR) with an acceptable safety profile that supports continued assessment in this heavily pretreated patient population. The preliminary results support further evaluation of duvelisib in patients with TCL, including additional studies in both CTCL and PTCL to determine the optimal dose and identify appropriate combination therapy. Disclosures Horwitz: Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, Spectrum•Consulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Off Label Use: ipi-145 is not an approved drug. Porcu:Actelion (e), Cutaneous Lymphoma Foundation (h), United States Cutaneous Lymphoma Consortium (h), Infinity (d), Celgene (d), : Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Infinity Pharmaceuticals: Consultancy. Kahl:Infinity Pharmaceuticals: Consultancy, Research Funding. Sweeney:Infinity Pharmaceuticals: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Douglas:Infinity Pharmaceuticals, Inc.: Employment. Allen:Infinity Pharmaceuticals: Employment. Kelly:Infinity Pharmaceuticals: Employment. Foss:Eisai, Celgene, Seattle Genetics: Consultancy, Research Funding, Speakers Bureau.

scholarly journals Pevonedistat, a Small Molecule Inhibitor of NEDD8-Activating Enzyme (NAE), Induces Cell Cycle Deregulation, Anaphase Catastrophe, and Apoptosis in T-Cell Lymphoma Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1667-1667
Author(s):  
Adam Kittai ◽  
Scott R Best ◽  
Taylor Rowland ◽  
Nur Bruss ◽  
Craig Okada ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Jurkat Cells ◽  
Lymphoma Cells ◽  
E3 Ligases ◽  
Cell Cycle Deregulation

Abstract Introduction: Despite the significant progress of targeted therapies in B-cell malignancies, T-cell lymphomas remain an area of unmet medical need. Most patients are diagnosed at an advanced stage and have limited treatment options. Moreover, most patients who relapse following initial chemotherapy ultimately succumb to disease. Recent successes of targeting the proteasome (i.e., bortezomib) and E3 ligases (i.e., lenalidomide) identify the ubiquitin-proteasome system (UPS) as a tractable target in lymphoma. Pevonedistat, an investigational small molecule inhibitor of NEDD8-activating enzyme (NAE), interferes with activation of NEDD8, a ubiquitin-like modifier. This interference ultimately leads to decreased activity of cullin-RING (E3) ligases and accumulation of their substrates, including inhibitor of NFκB (IκB), the replication licensing protein Cdt1, and p27. We previously demonstrated that targeting NAE affected primary neoplastic B cells via several mechanisms: disruption of NFκB activity as well as induction of Cdt1, DNA damage, and cell cycle arrest. Here, we demonstrate that targeting NAE in T-cell lymphoma cells mediates apoptosis via cell cycle deregulation, accompanied by induction of Cdt1 and p27, and induction of anaphase catastrophe. Methods: Experiments were performed in T-cell lymphoma cell lines (SR, HH, Jurkat, and SUP-T1) as well as circulating primary cells from patients with peripheral T-cell lymphoma and Sezary syndrome. Pevonedistat (TAK-924) was obtained from Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited (Cambridge, MA). Apoptosis was assessed by Annexin V staining. Results: SR (PTCL) cells and primary T-cell lymphoma cells were the most sensitive to pevonedistat (IC50of ~250nM at 24 hours); Jurkat and SUP-T1 cells demonstrated low/intermediate sensitivity, whereas HH (CTCL) cells were resistant. Targeting NAE disrupted cullin neddylation in a dose-dependent manner across all tested cell lines and primary neoplastic T cells, followed by accumulation of phospho-IκBα. Upregulation of phospho-IκBα was notable within 2 hours of pevonedistat treatment across both sensitive and resistant cell lines and primary cells. Concomitantly, we observed induction of p27 and Cdt1. Upregulation of Cdt1 was attenuated in HH cells compared with SR, consistent with the low proliferation rate of the former. Treatment of SR cells with pevonedistat led to DNA damage as evidenced by γH2AX and G2/M arrest. Chromosomal instability is a prominent feature in cancer and poorly studied as a therapeutic target. We have previously shown that cancer cells undergo multipolar anaphase in response to inhibition of cyclin-dependent kinase-2 (CDK2), an interphase CDK, followed by apoptosis and termed this event anaphase catastrophe (Hu et al., 2015; Danilov et al., 2016). As we observed robust accumulation of the endogenous CDK inhibitor p27 in cells treated with pevonedistat, an event presumed to lead to attenuated CDK2 activity, we studied anaphase catastrophe in this setting. We visualized anaphase catastrophe by immunofluorescent staining for nuclear material (DAPI) and γ-tubulin, and scored it in 50 cells per condition. NAE inhibition with pevonedistat induced anaphase catastrophe in SR and Jurkat cells. Upon 24-hour exposure to 250 nM pevonedistat, 9.8±6.0% of SR and 18±4.4% of Jurkat cells demonstrated multipolar anaphases, compared with 1±0.8% and 3.0±2.6% with vehicle control, respectively. Conclusions: Inhibiting NAE with pevonedistat induces apoptosis of T-cell lymphoma cells. We propose deregulation of Cdt1 and p27, followed by anaphase catastrophe, as a key mechanistic event implicated in pevonedistat-induced apoptosis in neoplastic T cells. Our work provides rationale to further investigate neddylation as a therapeutic target in T-cell lymphoma. Disclosures Danilov: Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Takeda Oncology: Research Funding; Gilead Sciences: Consultancy, Research Funding; Astra Zeneca: Consultancy; Aptose Biosciences: Research Funding; Bayer Oncology: Consultancy, Research Funding.

scholarly journals Autologous Stem Cell Transplantation for Angioimmunoblastic T-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-41
Author(s):  
Samer A. Srour ◽  
Yago Nieto ◽  
Swaminathan P Iyer ◽  
Roberto N. Miranda ◽  
Farzaneh Maadani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Prognostic Factors ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Advisory Committees ◽  
Angioimmunoblastic T Cell Lymphoma ◽  
Grant Support

Introduction: Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of rare neoplasms, the majority characterized by an aggressive course and short survival. Angioimmunoblastic T-cell lymphoma (AITL) is the second most common subtype (19%) of PTCLs, with generally poor long-term prognosis. The outcomes for most reported cases of AITL are derived from cohorts which include other PTCL subtypes. There is limited data for the role of autologous stem cell transplantation (ASCT) in AITL, and the associated predictive factors for prognosis. We present the largest single center cohort of AITL patients who underwent ASCT either upfront or at time of relapse. Methods: We included consecutive patients with AITL who had confirmed diagnosis and underwent ASCT at our institution from May 2000 to November 2019. Primary endpoints: progression free survival (PFS) and overall survival (OS). Secondary endpoints were cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and to identify prognostic factors associated with PFS and OS. Kaplan-Meier method was used to estimate OS and PFS. CIR and NRM were determined using the competing risks method. Cox regression analyses were used to determine prognostic factors. Results: The study included 54 patients with a median age of 63 (range, 37-77) years and male predominance (57%). All patients had advanced stage III/IV at diagnosis. Additional patient and disease characteristics are outlined in Table 1. Carmustine, etoposide, cytarabine, and melphalan (BEAM) with (30%) or without (57%) rituximab (R; used at the discretion of treating physician for EBER-positive AITL) were the most commonly used preparative regimens. With a median follow-up of 47.4 (range, 7.1-142.2) months, the median PFS and OS of all study patients were 41 and 108 months, respectively. The 2- and 4-year PFS/OS were 58%/83% and 46%/65%, respectively. CIR of relapse at 1, 2, and 4 years were 30%, 34%, and 44%, respectively. NRM at 1, 2, and 4 years were 7.5%, 7.5%, and 10%, respectively. All variables listed in Table 1 were assessed for their prognostic impact in univariate analysis (UVA) for PFS and OS. Of those, transplant for relapsed AITL (HR 3.716 95% CI: 1.728-7.991; p=0.0008) and high LDH at transplant (HR 2.139, 95% CI: 1.023-4.471; p=0.0433) were significantly associated with worse PFS (Figure 1A, C). There was a tendency for improved PFS for women (HR 0.56, 95% CI: 0.259-1.209; p=0.1398) and patients who received R-BEAM conditioning (HR for BEAM 1.99, 95% CI: 0.808-4.899; p=0.1344). Similar UVA results were noted for OS, where transplant for relapsed AITL (HR 2.943, 95% CI: 1.173-7.382; p=0.0214) and high LDH at transplant (HR 2.771, 95% CI: 1.076-7.138; p=0.0348) were significantly associated with worse OS (Figure 1B, D). On multivariable analysis (MVA), transplant at relapse (HR 3.716 95% CI: 1.728-7.991; p=0.0008) was associated with inferior PFS (HR 3.038, 95% CI: 1.386-6.659; p=0.0055) and OS (HR 2.291, 95% CI: 1.054-4.979; p=0.0364). High LDH at transplant was associated with worse PFS (HR 2.291, 95% CI: 1.054-4.979; p=0.0364), and with a trend for inferior OS (HR 2.259, 95% CI: 0.838-6.093; p=0.1073). Only 10 (19%) patients were transplanted with active disease at transplant; disease status at transplant didn't have a significant impact on outcomes in UVA and MVA. A subset analysis subgrouping patients by 1 (n=33) vs 2 (n=16) vs &gt;2 (n=5) prior lines of therapy showed no significant difference in outcomes between 2 vs &gt;2 prior lines of therapy. Conclusions: Upfront ASCT is associated with significantly improved and durable survival in patients with AITL. Receiving more than one prior line of therapy (transplant for relapsed AITL) and elevated LDH at transplant are associated with very poor prognosis, for which allogeneic transplant and alternative novel therapies should be further explored. Disclosures Nieto: Secura Bio: Other: Grant Support; Astra Zeneca: Other: Grant Support; Novartis: Other: Grant Support; Affimed: Consultancy, Other: Grant Support. Popat:Bayer: Research Funding; Novartis: Research Funding. Qazilbash:Angiocrine: Research Funding; Janssen: Research Funding; Bioline: Research Funding; Amgen: Research Funding; Bioclinica: Consultancy. Shpall:Takeda: Other: Licensing Agreement; Novartis: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Zelluna: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Cancer Prevention and Research Institute of Texas: Research Funding; Karyopharm: Consultancy; Pharmacyclics/Janssen: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Burroughs Wellcome Fund: Research Funding; TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; National Cancer Institute: Research Funding; V Foundation: Research Funding; Kite: Research Funding; Bayer: Consultancy; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; BeiGene: Consultancy; AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; OptumRx: Consultancy. Champlin:Johnson and Johnson: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Genzyme: Speakers Bureau; Cytonus: Consultancy; Omeros: Consultancy; Takeda: Patents & Royalties; Actinium: Consultancy. Hosing:NKARTA Inc.: Consultancy. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

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