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T-Cell Lymphoma: Recent Advances in Characterization and New Opportunities for Treatment Carla Casulo, Owen O’Connor, Andrei Shustov, Michelle Fanale, Jonathan W

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T-Cell Lymphoma: Recent Advances in Characterization and New Opportunities for Treatment Carla Casulo, Owen O’Connor, Andrei Shustov, Michelle Fanale, Jonathan W JNCI J Natl Cancer Inst (2017) 109(2): djw248 doi: 10.1093/jnci/djw248 First published online December 31, 2016 Review REVIEW T-Cell Lymphoma: Recent Advances in Characterization and New Opportunities for Treatment Carla Casulo, Owen O’Connor, Andrei Shustov, Michelle Fanale, Jonathan W. Friedberg, John P. Leonard, Brad S. Kahl, Richard F. Little, Lauren Pinter-Brown, Ranjani Advani, Steven Horwitz Affiliations of authors: Wilmot Cancer Center, University of Rochester, Rochester, NY (CC, JWF); Columbia University Medical Center, New York, NY (OO); Seattle Cancer Care Alliance, Seattle, WA (AS); University of Texas MD Anderson Cancer Center, Houston, TX (MF); Department of Medicine, Weil Cornell University, New York, NY (JPL); Oncology Division, Washington University, St. Louis, MO (BSK); Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (RFL); University of California-Irvine Chao Family Comprehensive Cancer Center in Orange, CA (LPB); Stanford Cancer Institute, Stanford University, Stanford, CA (RA); Memorial Sloan-Kettering Cancer Center, New York, NY (SH). Correspondence to: Carla Casulo, MD, Lymphoma Program, Wilmot Cancer Institute, University of Rochester, 601 Elmwood Avenue, Box 704, Rochester, NY 14642 (e-mail: [email protected]). REVIEW Abstract Peripheral T-cell lymphomas (PTCLs) are uncommon, heterogeneous, and aggressive non-Hodgkin’s lymphomas. Despite progress in the last several years resulting in a deeper understanding of PTCL biology and pathogenesis, there is currently no accepted single standard of care for newly diagnosed patients, and for those with relapsed or refractory disease, prognosis is dismal. The National Cancer Institute convened a Clinical Trials Planning Meeting to advance the national clinical trial agenda in lymphoma. The objective was to identify unmet needs specific to five major lymphoma subtypes and develop strategies to address them. This consensus statement reviews recent advances in the molecular and genetic characterization of PTCL that may inform novel treatments, proposes strategies to test novel therapies in the relapsed setting with the hopes of rapid advancement into frontline trials, and underscores the need for the identification and development of active and biologically rational therapies to cure PTCL at higher rates, with iterative biomarker evaluation. Recent Advances in Disease Characterization large cell lymphoma, ALK þ (ALKþ ALCL), 9% (3,4). Compared and Management with B cell NHL, PTCLs carry inferior outcomes. Despite gener- ally favorable response rates to chemotherapy, remissions are Epidemiology and Burden of Disease on Population often not durable, and as such the natural history of PTCL is characterized by relapses and, in some cases, refractory disease. Peripheral T-cell lymphomas (PTCLs) are a heterogeneous, un- For that reason, upfront hematopoietic stem cell transplanta- common, and often aggressive group of non-Hodgkin’s lympho- tion (HSCT) is often offered in first remission for patients who mas (NHL) representing approximately 10% to 15% of all new are fit and have chemosensitive disease. While phase II studies NHL diagnoses (1). The most recent iteration of the World suggest a benefit of this approach, it is unclear whether the su- Health Organization (WHO) classification describes over 20 dis- perior outcomes after HSCT are due to patient selection as op- tinct subtypes of PTCL (2). However, most incident cases are posed to a true benefit of HSCT (5,6). Unfortunately, many represented by the four most common subtypes: PTCL not oth- patients are either not candidates for transplantation or, con- erwise specified (NOS), 34%; angioimmunoblastic T-cell lym- versely, are unable to attain a response adequate enough to pro- phoma (AITL), 14%; anaplastic large cell lymphoma, anaplastic ceed to transplantation at the time of relapse. For these lymphoma kinase–negative (ALK- ALCL), 15%; and anaplastic patients, hopes of long-term disease control are very limited Received: April 19, 2016; Revised: July 14, 2016; Accepted: September 26, 2016 Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the United States. 1of9 C. Casulo et al. | 2 of 9 to 31%) and a two-year OS of 31% (95% CI ¼ 8% to 54%). Subsequently, many other treatment combinations are being actively explored in PTCL, with the goal of developing biologi- cally based rational therapeutic strategies. Areas of Recent Progress in Biological Understanding of Disease Recent advances in the molecular and genetic characterization of T-cell lymphomas have helped to delineate differences and simi- larities between the various subtypes. In the most recent World Health Organization (WHO) Classification of Lymphoid Neoplasms, multiple changes were made to the classification of both nodal and extranodal TCLs. Several recurrent mutations have Figure 1. In the relapsed setting, outcomes for peripheral T-cell lymphoma been identified in small subsets of patients. These genetic alter- (PTCL) are dismal. Noted here is a representative example from a recently com- ations are being grouped mechanistically and inform novel treat- pleted Southwest Oncology Group trial evaluating alisertib in relapsed/refrac- ments. As such, much of the additional genomic information tory PTCL (33). This figure is being published with permission from the original available is being included in the new WHO classification (15). authors and copyright holder. In PTCL NOS, a targeted deep-sequencing approach in 28 pa- tients revealed epigenetic deregulation as the most frequently (Figure 1), with progression-free survival (PFS) of 5.5 months (7). mutated category, followed by constitutive T-cell receptor (TCR) In this setting, optimal therapeutic approaches remain unde- activation as the most prominent genetic mechanisms in PTCL fined and represent an unmet clinical need. pathogenesis (16). Translocation t(5;9)(q33;q32) resulting in the Despite progress in the last several years resulting in a inducible T-cell kinase-spleen tyrosine kinase (ITK-SYK) fusion deeper understanding of PTCL, at present there is no accepted gene and leading to constitutive activation of the T-cell receptor single standard of care for newly diagnosed patients. The most was found in less than 10% of PTCL NOS (17). Similarly, the re- commonly used regimens have been derived from treatment of current translocation t(6:14) in PTCL juxtaposes the interferon aggressive B-cell NHL, such as cyclophosphamide, doxorubicin, regulatory factor 4 (IRF4) and the TCR alpha genes, resulting in vincristine, prednisone (CHOP); cyclophosphamide, doxorubi- overexpression of IRF4, driving MYC expression and contribut- cin, vincristine, etoposide, prednisone (CHOEP); or infusional ing to oncogenesis (18). Expression of the T-cell transcription etoposide, prednisone, vincristine, cyclophosphamide, doxoru- factor GATA-binding protein 3 (GATA 3) has been found to be el- bicin (EPOCH). Each appears to provide a similar overall re- evated in a subset of PTCLs and regulates the production of T sponse rate (ORR) of approximately 70% to 80%, with a complete helper cells and cytokine production, which are associated with REVIEW response (CR) rate of between 30% and 50% (5,6,8,9), and a five- poor outcomes (19). These findings have been recapitulated in year overall survival (OS) rate between 25% and 70%. When eval- genome-wide expression profiling, suggesting the presence of uated based on histology, however, outcomes are poorest for two distinct molecular subgroups of PTCL NOS: one character- AITCL and PTCL-NOS, and slightly better for ALCL (4,8,10–12). ized by increased GATA3 expression with poor prognosis and The National Clinical Trials Network (NCTN) has contributed the other by increased expression of t-box 21 (TBX21) transcrip- to the treatment landscape of PTCL with several recently com- tion factors and corresponding targets (20). pleted studies, although, with a few noted exceptions, therapeu- The enzyme isocitrate dehydrogenase 2 (IDH2) is a compo- tic strategies for PTCL have been largely unexplored by the nent of the Krebs cycle that normally catalyzes the conversion of NCTN. The Eastern Cooperative Oncology Group (ECOG) studied isocitrate to alpha-ketoglutarate, an intermediate for several en- the addition of humanized antivascular endothelial growth fac- zymes involved in epigenetic regulation and adaptation to hyp- tor antibody bevacizumab in combination with CHOP in the oxia. Neomorphic mutations in IDH2 result in production of E2404 study, given a role for angiogenesis in PTCL (13). This 2-hydroxyglutarate, an oncometabolite that represses histone 3 phase II study enrolled 46 patients, of whom 39 were evaluable lysine and DNA 5mC demethylation. In AITL, this represents the for response. While high overall response rates were observed third most common genetic lesion identified, after the Tet meth- with bevacizumab-CHOP, the regimen failed to yield durable re- ylcytosine dioxygenase 2 gene (TET2) and the Ras homolog gene missions and was associated with clinically significant and unac- family, member A (RHOA) mutations (21,22). TET2 mutations ceptable grade 3 and 4 toxicities including febrile neutropenia, were seen with a high frequency in AITL and PTCL NOS with a T congestive heart failure, venous thrombosis, and gastrointestinal follicular helper cell phenotype. Moreover, epigenetic alterations hemorrhage/perforation. At one year, progression-free survival and inactivating
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