scholarly journals Emerging Therapeutic Landscape of Peripheral T-Cell Lymphomas Based on Advances in Biology: Current Status and Future Directions

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5627
Author(s):  
Maliha Khan ◽  
Felipe Samaniego ◽  
Fredrick B. Hagemeister ◽  
Swaminathan P. Iyer
Keyword(s):  
T Cell ◽  
Molecular Mechanisms ◽  
Initial Therapy ◽  
Chemotherapeutic Agents ◽  
Current Status ◽  
Diverse Range ◽  
T Cell Lymphomas ◽  
Therapeutic Landscape ◽  
Pathologic Features ◽  
Relapsed Disease

T-cell lymphomas are a relatively rare group of malignancies with a diverse range of pathologic features and clinical behaviors. Recent molecular studies have revealed a wide array of different mechanisms that drive the development of these malignancies and may be associated with resistance to therapies. Although widely accepted chemotherapeutic agents and combinations, including stem cell transplantation, obtain responses as initial therapy for these diseases, most patients will develop a relapse, and the median survival is only 5 years. Most patients with relapsed disease succumb within 2 to 3 years. Since 2006, the USFDA has approved five medications for treatment of these diseases, and only anti-CD30-therapy has made a change in these statistics. Clearly, newer agents are needed for treatment of these disorders, and investigators have proposed studies that evaluate agents that target these malignancies and the microenvironment depending upon the molecular mechanisms thought to underlie their pathogenesis. In this review, we discuss the currently known molecular mechanisms driving the development and persistence of these cancers and discuss novel targets for therapy of these diseases and agents that may improve outcomes for these patients.

scholarly journals Genome-Based Identification of Cancer Genes by Proviral Tagging in Mouse Retrovirus-Induced T-Cell Lymphomas

2003 ◽  
Vol 77 (3) ◽  
pp. 2056-2062 ◽  
Author(s):  
Rachel Kim ◽  
Alla Trubetskoy ◽  
Takeshi Suzuki ◽  
Nancy A. Jenkins ◽  
Neal G. Copeland ◽  
...  
Keyword(s):  
T Cell ◽  
Molecular Mechanisms ◽  
Mouse Genome ◽  
Human Cancer ◽  
Inverse Pcr ◽  
Ras Signaling ◽  
Cancer Genes ◽  
Altered Expression ◽  
New Genes ◽  
T Cell Lymphomas

ABSTRACT The identification of tumor-inducing genes is a driving force for elucidating the molecular mechanisms underlying cancer. Many retroviruses induce tumors by insertion of viral DNA adjacent to cellular oncogenes, resulting in altered expression and/or structure of the encoded proteins. The availability of the mouse genome sequence now allows analysis of retroviral common integration sites in murine tumors to be used as a genetic screen for identification of large numbers of candidate cancer genes. By positioning the sequences of inverse PCR-amplified, virus-host junction fragments within the mouse genome, 19 target genes were identified in T-cell lymphomas induced by the retrovirus SL3-3. The candidate cancer genes included transcription factors (Fos, Gfi1, Lef1, Myb, Myc, Runx3, and Sox3), all three D cyclins, Ras signaling pathway components (Rras2/TC21 and Rasgrp1), and Cmkbr7/CCR7. The most frequent target was Rras2. Insertions as far as 57 kb away from the transcribed portion were associated with substantially increased transcription of Rras2, and no coding sequence mutations, including those typically involved in Ras activation, were detected. These studies demonstrate the power of genome-based analysis of retroviral insertion sites for cancer gene discovery, identify several new genes worth examining for a role in human cancer, and implicate the pathways in which those genes act in lymphomagenesis. They also provide strong genetic evidence that overexpression of unmutated Rras2 contributes to tumorigenesis, thus suggesting that it may also do so if it is inappropriately expressed in human tumors.

scholarly journals Primary Cutaneous Acral CD8+ T-Cell Lymphoma

2017 ◽  
Vol 141 (11) ◽  
pp. 1469-1475 ◽  
Author(s):  
Vivian M. Hathuc ◽  
Alexandra C. Hristov ◽  
Lauren B. Smith
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Correct Diagnosis ◽  
Cd8 T Cell ◽  
T Cell Lymphoma ◽  
World Health ◽  
T Cell Lymphomas ◽  
Pathologic Features ◽  
Health Organization

Primary cutaneous acral CD8+ T-cell lymphoma is a new provisional entity in the 2016 revision of the World Health Organization classification of lymphoid neoplasms. This is a challenging diagnosis because of its rarity, as well as its morphologic and immunophenotypic overlap with other CD8+ cytotoxic lymphoid proliferations. Appropriate classification of this entity is crucial because of its indolent clinical behavior compared with other CD8+ T-cell lymphomas. Knowledge of the clinical setting, sites of involvement, and morphologic features can aid in correct diagnosis. Here, we review the clinical and pathologic features of primary cutaneous acral CD8+ T-cell lymphoma with an emphasis on the differential diagnosis among other C8+ T-cell lymphomas.

scholarly journals Mycosis Fungoides and Sézary Syndrome: An Integrative Review of the Pathophysiology, Molecular Drivers, and Targeted Therapy

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1931
Author(s):  
Nuria García-Díaz ◽  
Miguel Ángel Piris ◽  
Pablo Luis Ortiz‐Romero ◽  
José Pedro Vaqué
Keyword(s):  
T Cell ◽  
Mycosis Fungoides ◽  
T Cell Receptor ◽  
Molecular Mechanisms ◽  
Cell Receptor ◽  
Janus Kinase ◽  
Sézary Syndrome ◽  
Sezary Syndrome ◽  
Signal Transducer ◽  
T Cell Lymphomas

Primary cutaneous T-cell lymphomas (CTCLs) constitute a heterogeneous group of diseases that affect the skin. Mycosis fungoides (MF) and Sézary syndrome (SS) account for the majority of these lesions and have recently been the focus of extensive translational research. This review describes and discusses the main pathobiological manifestations of MF/SS, the molecular and clinical features currently used for diagnosis and staging, and the different therapies already approved or under development. Furthermore, we highlight and discuss the main findings illuminating key molecular mechanisms that can act as drivers for the development and progression of MF/SS. These seem to make up an orchestrated constellation of genomic and environmental alterations generated around deregulated T-cell receptor (TCR)/phospholipase C, gamma 1, (PLCG1) and Janus kinase/ signal transducer and activator of transcription (JAK/STAT) activities that do indeed provide us with novel opportunities for diagnosis and therapy.

Autologous and allogeneic transplantation for aggressive T-cell lymphomas: A single institution experience

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8558-8558
Author(s):  
F. Lansigan ◽  
D. Cooper ◽  
S. Seropian ◽  
F. Foss
Keyword(s):  
T Cell ◽  
Nk Cell ◽  
Cell Transformation ◽  
Progression Free Survival ◽  
Large Cell ◽  
Allogeneic Transplantation ◽  
Non Hodgkin Lymphoma ◽  
T Cell Lymphomas ◽  
First Remission ◽  
Relapsed Disease

8558 Aggressive T-cell lymphomas (ATCL) represent 10–15% of non-Hodgkin lymphoma and have a worse prognosis than aggressive B-cell lymphomas. Both autologous (Auto) and allogeneic (Allo) stem cell transplantation have been used as consolidation in first remission and at relapse, but the role of transplantation has not been clearly defined. There were 24 Auto and 18 Allo between 8/1997 and 12/2007. The Allo group consisted of 4 PTCLu, 3 angioimmunoblastic(AITL), 2 panniculitis-like, 2 cutaneous(CTCL) with large cell transformation, 2 NK-cell, 2 anaplastic large cell(ALCL), 1 hepatosplenic, 1 enteropathic, and 1 refractory CTCL. The Auto group consisted of 6 PTCLu, 12 ALCL (5 Alk+, 5 Alk-, 2 Alk unk), 4 AITL, 1 CTCL with transformation, and 1 T-lymphoblastic lymphoma. The median age was 51y(Allo) and 52y(Auto). Median prior therapies were 3(Allo) and 1(Auto). There were 14 matched- and 4 matched-unrelated Allo transplants; 7 were ablative and 11 were reduced-intensity. Median time from diagnosis to Allo or Auto was 18 and 8mo, respectively. Median follow-up was 29mo (Allo) and 24mo (Auto). The day 100 TRM was 11%(Allo) and 4%(Auto) respectively. The relapse mortality was 11%(Allo) and 33%(Auto). The non-relapse mortality was 33%(Allo) and 8%(Auto). The 1- and 2-year overall survival(OS) rates were similar within the Allo and Auto groups (78% vs 74%, and 67% vs 60% respectively). The 1- and 2-year progression-free survival (PFS) for the Allo vs Auto groups were 68% vs 52%, and 53% vs 45%, respectively (p=0.28). Within the Auto group, 14(58%) were transplanted in first complete remission(CR1), and 10(42%) in CR2, beyond CR2, or PR. Patients in CR1 had significantly better PFS (57 vs 17mo, p=0.007) and OS (76 vs 29mo, p=0.004) than those in CR2, beyond CR2, or PR. Allo patients with prior Auto(6) had a poorer OS than patients with no prior Auto(12), 32 vs 60mo, respectively, but the results were not statistically significant, p=0.15. One Allo was transplanted in CR1 and is still alive at 33mo. We conclude that outcomes for Auto are best in CR1. For patients with resistant or relapsed disease, Allo should be strongly considered rather than Auto. These results also suggest that a prospective randomized trial comparing Auto and Allo for ATCL in first remission is warranted. No significant financial relationships to disclose.

T-cell non-Hodgkin lymphoma

Blood ◽  
2006 ◽  
Vol 107 (4) ◽  
pp. 1255-1264 ◽  
Author(s):  
Mujahid A. Rizvi ◽  
Andrew M. Evens ◽  
Martin S. Tallman ◽  
Beverly P. Nelson ◽  
Steven T. Rosen
Keyword(s):  
T Cell ◽  
Viral Infections ◽  
Chromosomal Translocations ◽  
Non Hodgkin Lymphoma ◽  
T Cell Lymphomas ◽  
Pathologic Features ◽  
Tremendous Progress ◽  
Diagnostic Work ◽  
Work Up ◽  
Made In

T-cell non-Hodgkin lymphomas (NHLs) are uncommon malignancies. The current WHO/EORTC classification recognizes 9 distinct clinicopathologic peripheral T-cell NHLs. These disorders have unique characteristics and require individualized diagnostic and therapeutic strategies. Tremendous progress has been made in recent years in the understanding of the pathogenesis of these disorders. Specific chromosomal translocations and viral infections are now known to be associated with certain lymphomas. In this review, we describe their clinical and pathologic features. We also discuss the use of molecular studies in the diagnostic work-up of T-cell lymphomas. Because of the rarity of these disorders and the lack of well-designed clinical trials, the treatment of peripheral T-cell NHLs is often challenging. Additional studies are required to learn more about the biology of these diseases, which may lead to more optimal and possibly targeted therapies.

Clinico-pathologic features and outcome of Japanese patients with peripheral T-cell lymphomas

2008 ◽  
Vol 26 (3) ◽  
pp. 152-158 ◽  
Author(s):  
Nozomi Niitsu ◽  
Masataka Okamoto ◽  
Hirokazu Nakamine ◽  
Sadao Aoki ◽  
Shigeki Motomura ◽  
...  
Keyword(s):  
T Cell ◽  
Japanese Patients ◽  
T Cell Lymphomas ◽  
Pathologic Features ◽  
Peripheral T Cell Lymphomas

Hepatosplenic T-Cell Lymphoma: Clinicopathological Features and Treatment Outcomes: Report From The North American Peripheral T-Cell Lymphoma Consortium

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3032-3032 ◽  
Author(s):  
Andrei R. Shustov ◽  
Wyndham H Wilson ◽  
Anne W Beaven ◽  
Kerry J. Savage ◽  
Kenneth R. Carson ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cell Lymphoma ◽  
Initial Therapy ◽  
T Cell Lymphoma ◽  
Treatment Regimens ◽  
T Cell Lymphomas ◽  
Rare Malignancy

Abstract Background Hepatosplenic T-cell lymphoma (HSTCL) is an exceedingly rare subtype of mature T-cell lymphomas with dismal outcome despite combination chemotherapies. It is characterized by frequent involvement of splenic red pulp, liver sinusoids and bone marrow; nodal and other extranodal sites are rarely affected. Patients frequently present with cytopenias and B–symptoms. Malignant cells are medium-sized mature T-cells with cytotoxic phenotype. Most frequent chromosomal abnormalities are isochromosome 7q and trisomy 8. Gamma-delta phenotype is found in the majority of cases, but alpha-beta variant has been reported. All studies to date report very poor responses to standard lymphoma protocols and only few survivors after stem cell transplantation. We report the largest series of this rare malignancy to date including clinicopathologic features and treatment outcomes collected by several North American Institutions. Methods This is a retrospective multi-center cohort study conducted by the participating institutions. Data was collected from charts of previously diagnosed and treated HSTCL patients. Chart review protocol was approved by Institutional Review Boards of participating centers and a waiver of consent was obtained. University of Washington served as coordinating center for data collection and analysis. We obtained the following data from patients' medical charts: demographic characteristics, histologic findings, immunophenotypic and molecular analysis, cytogenetics, treatment regimens and disease responses, clinical outcomes and survival. Summary statistics was used to describe the clinical, demographic and pathological characteristics. Response was defined using the International Workshop NHL criteria. For survival analyses, overall survival (OS) was time between the diagnosis and the patient's last follow up or death. The Kaplan-Meier method was used to estimate survival distributions. Results Forty-two patients were identified, 24 male and 18 female, with the median age of 35 (range, 17-79) years. Twenty-six (62%) patients were Caucasian, 8 (19%) were Asian, 6 (14%) were African American, and 2 (5%) were other. Splenomegaly was reported in 39/42 patients (93%), hepatomegaly in 23/40 (58%), and bone marrow involvement in 32/39 (82%) patients. Lymph nodes were involved in only 12/40 (30%) patients. Anemia was present (median HCT=30.5%) in 30/37 (81%), leucopenia (median WBC=4.3K/ul) in 9/41 (22%), thrombocytopenia (median platelet count = 80K/ul) in 33/41 (80%) of reported patients. Abnormal liver function tests were found in 31/38 (82%) of the reported cases. Gamma-delta and alpha-beta phenotype was found in 84% and 16% of reported cases (n=37), respectively. Isochromosome 7q was found in 6/23 (26%) of patients while 6/23 (26%) had other aberrations. History of immunosuppressive therapy was present in 13/42 (31%) reported patients, including 4 patients receiving prior therapy with TNF-alpha inhibitors. Nine out of 42 patients (21%) had history of inflammatory bowel disease. All patients received multi-agent chemotherapy. Overall response rate (ORR) to initial therapy was 63%, with 44% achieving complete remission (CR). Twenty-three out of 42 (55%) reported patients underwent autologous (n=2) or allogeneic (n=19) stem cell transplantation, and 2 underwent both. Twenty-nine (69%) patients have died. Of note, all but one of the surviving patients have undergone allogeneic stem cell transplantation. With the median follow-up of 56 (range 15-105) mo for living patients, the median OS was 15.8 mo (Fig. 1). Detailed histo-pathologic data and treatment regimens will be reported at the meeting. Conclusions This is the largest study to date of hepatosplenic T-cell lymphomas. This is a rare malignancy associated with poor outcomes after contemporary treatments. Response to initial therapies is suboptimal, relapses are frequent and median overall survival is short. Stem cell transplantation in first remission should be considered for all patients achieving response to initial therapy. Novel therapies are needed to improve outcomes. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Strategies to Overcome Resistance Mechanisms in T-Cell Acute Lymphoblastic Leukemia

2019 ◽  
Vol 20 (12) ◽  
pp. 3021 ◽  
Author(s):  
Elena Follini ◽  
Matteo Marchesini ◽  
Giovanni Roti
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Nuclear Export ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Resistance Mechanisms ◽  
Chemotherapeutic Agents ◽  
Cyclin D3 ◽  
Cancer Drug ◽  
Cell Acute Lymphoblastic Leukemia

Chemoresistance is a major cause of recurrence and death from T-cell acute lymphoblastic leukemia (T-ALL), both in adult and pediatric patients. In the majority of cases, drug-resistant disease is treated by selecting a combination of other drugs, without understanding the molecular mechanisms by which malignant cells escape chemotherapeutic treatments, even though a more detailed genomic characterization and the identification of actionable disease targets may enable informed decision of new agents to improve patient outcomes. In this work, we describe pathways of resistance to common chemotherapeutic agents including glucocorticoids and review the resistance mechanisms to targeted therapy such as IL7R, PI3K-AKT-mTOR, NOTCH1, BRD4/MYC, Cyclin D3: CDK4/CDK6, BCL2 inhibitors, and selective inhibitors of nuclear export (SINE). Finally, to overcome the limitations of the current trial-and-error method, we summarize the experiences of anti-cancer drug sensitivity resistance profiling (DSRP) approaches as a rapid and relevant strategy to infer drug activity and provide functional information to assist clinical decision one patient at a time.

HIV-Associated NK/T-Cell Lymphomas: A Review of 93 Cases.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3457-3457
Author(s):  
Jorge Castillo ◽  
Liron Pantanowitz
Keyword(s):  
T Cell ◽  
Nk Cell ◽  
Large Cell ◽  
Tumor Location ◽  
Cd4 Count ◽  
Comprehensive Review ◽  
Male Predominance ◽  
T Cell Lymphomas ◽  
Pathologic Features ◽  
Nk T Cell

Abstract Introduction: NK/T-cell lymphomas (NKTCL) are being reported with increased frequency in HIV-infected patients in the HAART era. However, there has been no comprehensive review of these emerging HIV-associated lymphomas. We present, to our knowledge, the first comprehensive review of the epidemiology, clinical and pathologic features, therapeutic options, and outcome in HIV-associated NKTCL. Methods: A total of 93 cases of NKTCL in HIV-infected individuals were identified in a literature review using PubMed and cited articles from 1996 until March 2007. Data regarding epidemiology (country), demographics (age, gender), clinical features (presentation, tumor location), HIV status (CD4, AIDS-defining illness, coinfections), lymphoma (WHO/EORTC subtype, immunophenotype, Ann Arbor stage), treatment, and outcome were extracted. Results: Cases were reported worldwide (USA, Europe, South America, Asia), with a 15x increased incidence compared to the general population. Patients were of median age 38 years (range 1–63) at presentation, exhibited a 4:1 male predominance, and had a median CD4 count of 184 cells/mm3. Up to 54% had a prior AIDS-defining illness. The most common clinical findings were lymphadenopathy, B symptoms, erythroderma and pruritus. All subtypes were noted including Peripheral T-cell (n=36), Cutaneous T-cell including Mycosis fungoides (n=25), Anaplastic Large Cell (n=13), Adult T-cell Leukemia/Lymphoma (n=8), NK cell (n=4), and other lymphomas (2 AILD, 2 Enteropathy-associated, 1 PEL, 1 Intravascular). Most expressed CD45RO and CD3 antigens, CD4>CD8, CD30 in a subset (n=23), and EBV was detected in 20 cases (mainly extranodal PTCL, cutaneous ALCL, and NK cells). Most (74%) were extranodal (50% involving skin) and 26% nodal. Staging (60 patients) overall showed stage I (27%), II (3%), III (17%), and IV (53%).There was no standard therapeutic approach, with 46% given one modality, 17% multimodal treatment, and 12% were untreated in reported cases. HAART was rarely used. Death occurred in 55% of patients and median overall survival (83 patients) was 1.1 years from the time of diagnosis. Conclusions: NKTCL afflicted HIV-infected persons are likely to be young males with AIDS who have a CD4 count under 200 cells/mm3 at presentation. They are also prone to present with extranodal disease, skin involvement, and at an advanced stage. Although a standard treatment approach is still required, the prognosis of HIV-associated NKTCL remains poor. The role of HAART needs to be further explored.

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