Critical Reviews in Oncology/Hematology 99 (2016) 214–227 CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Contents lists available at ScienceDirect Critical Reviews in Oncology/Hematology jo urnal homepage: www.elsevier.com/locate/critrevonc Panoptic clinical review of the current and future treatment of relapsed/refractory T-cell lymphomas: Peripheral T-cell lymphomas a,∗ b c c d Pier Luigi Zinzani , Vijayveer Bonthapally , Dirk Huebner , Richard Lutes , Andy Chi , e,f Stefano Pileri a Institute of Hematology ‘L. e A. Seràgnoli’, Policlinico Sant’Orsola-Malpighi, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy b 1 Global Outcomes and Epidemiology Research (GOER), Millennium Pharmaceuticals Inc., 40 Lansdowne Street, Cambridge, MA 02139, USA c 1 Oncology Clinical Research, Millennium Pharmaceuticals Inc., 35 Lansdowne Street, Cambridge, MA 02139, USA d 1 Department of Biostatistics, Millennium Pharmaceuticals Inc., 40 Lansdowne Street, Cambridge, MA 02139, USA e Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University School of Medicine, Via Massarenti 8, 40138 Bologna, Italy f Unit of Hematopathology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy Contents 1. Introduction . 214 2. Methodology. .215 3. Treatment of relapsed/refractory PTCL . 215 3.1. Conventional chemotherapy in relapsed/refractory PTCL. .215 3.2. Approved therapies in relapsed/refractory PTCL . 216 3.3. Investigational and off-label therapies in relapsed/refractory PTCL . 222 4. Concluding remarks . 224 Conflict of interest . 224 Funding . 224 Acknowledgments. .224 References . 224 Biography . 227 a r t i c l e i n f o a b s t r a c t Article history: Peripheral T-cell lymphomas (PTCLs) tend to be aggressive and chemorefractory, with about 70% of Received 29 June 2015 patients developing relapsed/refractory disease. Prior to 2009, chemotherapies were the only options for Received in revised form relapsed/refractory PTCL, other than hematopoietic transplants. However, chemotherapy only improves 11 November 2015 survival by about 1 month compared with palliation. Four drugs are now approved in the US to treat Accepted 23 December 2015 relapsed/refractory PTCL: pralatrexate, romidepsin, belinostat, and brentuximab vedotin (for systemic anaplastic large cell lymphoma [sALCL]). Response rates with pralatrexate, romidepsin, and belinostat Keywords: range from 25 to 54% in mixed relapsed/refractory PTCL populations, while 86% of sALCL patients respond Adult T-cell leukemia/lymphoma to brentuximab vedotin. Here, we critically evaluate the evidence supporting the current drug treatment Anaplastic large cell lymphoma of relapsed/refractory PTCL, and look to the future to see how the treatment panorama may change Angioimmunoblastic T-cell lymphoma Belinostat with the advent of new targeted therapies, some of which (e.g., alisertib in PTCL and mogamulizumab in Brentuximab vedotin CCR4-positive adult T-cell leukemia/lymphoma) are already in phase 3 trials. Peripheral T-cell lymphoma © 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC Pralatrexate BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Romidepsin 1. Introduction T-cell lymphomas (TCLs) represent a heterogeneous yet rare group of non-Hodgkin lymphomas (NHLs). Such malignancies are ∗ Corresponding author. Fax: +39 0516364037. conventionally divided into two classes according to their origin: E-mail address: [email protected] (P.L. Zinzani). peripheral TCLs (PTCLs), the most common class of TCL (Karlin and 1 A wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. http://dx.doi.org/10.1016/j.critrevonc.2015.12.016 1040-8428/© 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). P.L. Zinzani et al. / Critical Reviews in Oncology/Hematology 99 (2016) 214–227 215 Coiffier, 2014), which arise from clonal proliferation of mature post- regimens that can overcome resistance to conventional chemother- thymic T cells (Karlin and Coiffier, 2014; Dearden et al., 2015); apy, are helping to improve outcomes. and cutaneous TCLs (CTCLs), which arise from malignant clonal In this paper, we attempt to comprehensively review the cur- transformation of mature skin-homing and/or skin-resident T cells rent treatment landscape for relapsed/refractory PTCL, focusing in (Guenova et al., 2014). particular on the new and exciting clinical data on novel targeted PTCLs represent <15% of all NHLs (Karlin and Coiffier, 2014), therapies and chemotherapy regimens. We also look forward to the with a prevalence that varies considerably according to geography, future by exploring the potential of investigational therapies that including a particularly high rate in East Asia due to viral (Epstein- are in various stages of clinical development for PTCL. Barr virus [EBV] and human T-cell leukemia virus-1 [HTLV-1]) association (Reddy and Evens, 2014; Vose et al., 2008; Foss et al., 2. Methodology 2011). In the United States, it is estimated that PTCL affects <1 in 100,000 people (Morton et al., 2006), with approximately 9500 new A literature search was undertaken to identify clinical studies cases diagnosed each year (Malik et al., 2010). Over recent years, reporting efficacy outcomes following conventional and investiga- the incidence of PTCL appears to be increasing in both Western and tional pharmacologic therapies in patients with relapsed and/or Asian countries (Chihara et al., 2012; Sharaiha et al., 2012), probably refractory PTCL, defined according to the WHO 2008 classifica- as a consequence of the aging population and improved diagnos- tion. MEDLINE (PubMed) was searched for studies published up tics. PTCLs are mainly diagnosed in the over-50s, but median age to February 6, 2015, and bibliographies of recent systematic and at presentation can vary between subtypes (Lunning and Horwitz, treatment reviews (2011–14) were searched manually. Confer- 2013). These malignancies also tend to be more common in men ence proceedings from the American Society of Clinical Oncology than women (Lunning and Horwitz, 2013). (ASCO), American Society of Hematology (ASH), European Society According to the 2008 World Health Organization (WHO) clas- for Medical Oncology (ESMO), and European Hematology Associ- sification, PTCLs can be subdivided into three major subgroups ation (EHA) annual meetings (2013–14) were also interrogated. (nodal, extranodal, and leukemic) and 14 distinct entities based ‘Peripheral T-cell lymphoma’ and distinct WHO-defined PTCL dis- on clinical features and pathologic phenotype (Fig. 1) (Karlin and ease entities (Fig. 1) were used as search terms. Publication titles Coiffier, 2014; Foss et al., 2011). The most commonly encountered and abstracts were screened to identify clinical studies of drug PTCL diagnoses, accounting for more than half of all cases, are therapies in relapsed and/or refractory PTCLs. There were no fast-growing nodal malignancies, such as PTCL-not otherwise spec- restrictions regarding study design or treatment, although prospec- ified (PTCL-NOS; a group of lymphomas that do not fit into any tive trials were selected preferentially; frontline studies were of the other classifications of PTCL) (25.9%), angioimmunoblastic excluded. Despite no formal analysis, data were extracted on study T-cell lymphoma (AITL) (18.5%; a PTCL subtype often associated type, patients, diagnosis, prior treatments, and efficacy outcomes with viral infection), and systemic anaplastic large cell lymphoma (response rates, duration of response, progression-free survival (sALCL) (12.1%), which can be subdivided into anaplastic lymphoma [PFS], and OS). kinase (ALK)-positive (ALK+; 6.6%; a more indolent malignancy) and ALK-negative (ALK−; 5.5%; a rapidly progressing malignancy) 3. Treatment of relapsed/refractory PTCL forms depending on the presence or absence of an abnormal form of the ALK protein on the surface of malignant T cells (Karlin and The rarity of PTCL and the lack of randomized controlled trials Coiffier, 2014; Vose et al., 2008; Foss et al., 2011). Other subtypes of mean there is currently little consensus regarding optimal therapy PTCL include extranodal natural killer (NK)/T-cell lymphoma, nasal for the majority of PTCL entities. Historically, management strate- type (NKTCL) (10.4%; a class of malignancies linked with EBV infec- gies for PTCL have been derived from studies of predominantly tion that is generally classified as a PTCL subtype despite some B-cell NHL that only included small numbers of patients with PTCL. being derived from NK cells), adult T-cell leukemia/lymphoma Guideline recommendations for treatment are also often based (ATLL) (9.6%; a malignancy associated with HTLV-1 infection), and on small case series, phase 2 trials, and expert opinion (Dearden enteropathy-associated T-cell lymphoma (EATL) (4.7%; a PTCL sub- et al., 2015; National Cancer Institute, 2015a; Dreyling et al., 2013). type frequently, but not always associated with celiac disease) Because it is difficult to recruit patients, most clinical trials of new (Karlin and Coiffier, 2014; Vose et al., 2008; Lunning and Horwitz, 2013). agents and regimens in PTCL have enrolled patients with a range of diagnoses, and very few studies have focused specifically on single The majority of PTCLs (except for ALK+ sALCL) tend to be disease entities. Interpretation of data,