Peripheral T-Cell Lymphomas

Critical Reviews in Oncology/Hematology 99 (2016) 214–227

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Critical Reviews in Oncology/Hematology

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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

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

Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University School of Medicine, Via Massarenti 8, 40138 Bologna, Italy

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.

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

A wholly owned subsidiary of Takeda Pharmaceutical Company Ltd.

http://dx.doi.org/10.1016/j.critrevonc.2015.12.016

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, particularly in older studies,

aggressive and chemorefractory, and many patients have a gloomy

is also hampered by the historical lack of a uniform classiﬁcation,

prognosis, with 5-year survival rates in patients with PTCL-NOS

potential misdiagnosis, and the use of different criteria to assess

or AITL estimated at approximately 30% (Karlin and Coifﬁer,

anti-lymphoma response.

2014; Vose et al., 2008). The frontline treatment approach for

PTCL, albeit transiently effective (Karlin and Coifﬁer, 2014), varies

between diagnoses, but for most subtypes comprises combi- 3.1. Conventional chemotherapy in relapsed/refractory PTCL

nation chemotherapy (most commonly CHOP, CHEOP, or other

anthracycline-based multidrug regimens, such as EPOCH and Until recently, conventional systemic chemotherapies remained

HyperCVAD), with autologous stem cell transplantation (ASCT) the only salvage options for patients with relapsed/refractory PTCL,

given as consolidation for selected patients (but not in ALK+ sALCL aside from ASCT or allogeneic stem cell transplantation (allo-SCT),

patients) (National Cancer Institute, 2015a; Dreyling et al., 2013). the discussion of which is beyond the scope of this review (fur-

Unfortunately, most patients with TCLs who undergo induction ther information on the key role of hematopoietic transplantation

treatment (70%) will go on to develop relapsed and/or refractory in treating relapsed/refractory PTCL is provided in a number of

disease (Dreyling et al., 2013). These patients can be particularly recent reviews (Perrone et al., 2013; Perrone and Corradini, 2014;

difﬁcult to treat – median overall survival (OS) among non- Schmitz et al., 2014; Gkotzamanidou and Papadimitriou, 2014)).

transplanted, relapsed/refractory patients with PTCL is 5.5 months Unfortunately, the data to support the use of chemotherapy is weak,

(Mak et al., 2013) – although new advances in therapy, such as it is frequently derived from retrospective studies and/or older

as molecularly targeted treatments that disrupt the underlying prospective studies in which patient diagnoses are unclear or not

mechanisms of disease, and novel chemotherapeutic agents and speciﬁed, and sample sizes are limited.

216 P.L. Zinzani et al. / Critical Reviews in Oncology/Hematology 99 (2016) 214–227

Mature T-/NK-cell neoplasms

Cutaneous Extranodal Nodal Leukemic

Mycosis fungoides NK/T-cell lymphoma, Anaplastic large-cell Adult T-cell leukemia/ nasal type lymphoma (ALK+) lymphoma Primary cutaneous CD30+ LPDs Subcutaneous Peripheral TCL-NOS Aggressive NK-cell (lymphomatoid papulosis, panniculitis-like TCL leukemia

primary cutaneous anaplastic (alpha/beta type) Angioimmunoblastic TCL

large-cell lymphoma) T-cell prolymphocytic Enteropathy-associated Anaplastic large-cell leukemia Sézary syndrome TCL lymphoma (ALK–) T-cell large granular Primary cutaneous Hepatosplenic lymphocytic leukemia gamma/delta type gamma/delta TCL

Primary cutaneous Systemic EBV+ CD8+ aggressive childhood TCL epidermotropic TCL Hydroa vacciniforme-like Primary cutaneous lymphoma CD4+ small/medium TCL

Indolent Aggressive

Fig. 1. World Health Organization 2008 classiﬁcation of mature T-cell lymphomas: peripheral T-cell lymphomas (Swerdlow et al., 2008).

+, positive; −, negative; ALK, anaplastic lymphoma kinase; EBV, Epstein-Barr virus; LPD, lymphoproliferative disorders; TCL, T-cell lymphoma; NK, natural killer; NOS, not

otherwise speciﬁed.

Combination regimens that are sometimes used to treat younger of the intensive SMILE regimen (dexamethasone, methotrexate,

ﬁtter patients with relapsed/refractory PTCL, either as stan- ifosfamide, l-asparaginase/pegaspargase, and etoposide) and its

dalone salvage treatment or as a bridge to ASCT or allo-SCT, various modiﬁcations, all of which contain l-asparaginase or pegas-

include (National Cancer Institute, 2015a): DHAP (dexametha- pargase as the key component, to treat relapsed/refractory patients

sone, cisplatin, and cytarabine) (Velasquez et al., 1988; Mey with extranodal NKTCL, nasal type (Yamaguchi et al., 2008, 2011;

et al., 2006); ESHAP (etoposide, methylprednisolone, cytarabine, Kwong et al., 2012; Jaccard et al., 2011). These regimens are asso-

and cisplatin) (Velasquez et al., 1994); dose-adjusted EPOCH ciated with high ORRs (>60%), but tolerability is an issue for many

(etoposide, prednisone, vincristine, cyclophosphamide, and dox- patients due to the high risk of hematologic toxicity, nephrotoxicity,

orubicin) (Wilson et al., 1993); ICE (ifosfamide, carboplatin, and hepatotoxicity, and infection (Yamaguchi et al., 2011; Kwong et al.,

etoposide) (Zelenetz et al., 2003); MINE (mesna, ifosfamide, 2012). Nevertheless, l-asparaginase/pegaspargase-containing reg-

mitoxantrone, and etoposide) (Dincol et al., 2010; Mayer et al., imens are now recommended as the mainstay of therapy for this

1999); and gemcitabine-based regimens, such as GDP (gemc- rare and difﬁcult-to-treat PTCL subtype (National Cancer Institute.,

itabine, dexamethasone, and cisplatin), GemOx (gemcitabine and 2015a).

oxaliplatin), GND (gemcitabine, vinorelbine, and doxorubicin),

and GEM-P (gemcitabine, cis-platinum, and methylprednisolone)

3.2. Approved therapies in relapsed/refractory PTCL

(Emmanouilides et al., 2004; Ng et al., 2005; Arkenau et al., 2007;

López et al., 2008; Dong et al., 2013; Park et al., 2015). With these

While conventional chemotherapies remain important thera-

regimens, the overall response rate (ORR) rarely exceeds 50%, the

peutic options in this setting, four next-generation drugs have

duration of response is short, and only a few patients achieve

recently been approved in the United States, speciﬁcally for use

a complete response (CR) (Dreyling et al., 2013). Furthermore, a

in patients with relapsed and/or refractory PTCL (Table 1). The ﬁrst

recent retrospective study suggests that use of chemotherapy regi-

of these compounds is pralatrexate, an intravenous (IV) antifolate

mens following relapse or progression on frontline therapy in PTCL

chemotherapy with high afﬁnity for the reduced folate carrier-1

patients (with PTCL-NOS, sALCL, or AITL) only improves median OS

receptor and folypolyglutamate synthase, which exhibits greater

by 1 month compared with no active treatment (Mak et al., 2013).

cytotoxic potency than either of the ﬁrst-generation antifolates,

For single-agent use in older and more vulnerable patients,

methotrexate or edatrexate (Wang et al., 2003; Sirotnak et al., 1998;

including those with relapsed/refractory NKTCL, gemcitabine

Shimanovsky and Dasanu, 2013). This agent acts to inhibit dihy-

appears to be one of the most commonly used and most active

drofolate reductase and thymidylate synthase, and thereby disrupt

chemotherapies (Zinzani et al., 1998; Sallah et al., 2001; Zinzani

the DNA/RNA synthesis required for lymphoma cell proliferation

et al., 2000, 2010; Ahn et al., 2013). Originally used because of its

(Sirotnak et al., 1998; Shimanovsky and Dasanu, 2013). Pralatrex-

activity in CTCL (Zinzani et al., 2000), single-agent gemcitabine has

ate is currently indicated for the treatment of patients with relapsed

shown evidence of activity in PTCL, including a 55% ORR and 30%

or refractory PTCL (FOLOTYN , 2012). The second approved agent

CR rate in patients with PTCL-NOS (Zinzani et al., 2010).

is romidepsin, a potent IV class 1 histone deacetylase (HDAC)

In terms of speciﬁc PTCL entities, single-agent cyclosporine may

inhibitor that acts to prevent gene transcription and disrupt pro-

beneﬁt patients with relapsed/refractory AITL, although the evi-

tein function in malignant lymphoma cells by interfering with the

dence supporting its use is limited to case series and case reports

acetylation pattern of chromatin on histone lysine residues (Khot

(Advani et al., 2007). There is more evidence to support the use

et al., 2013a). Romidepsin is approved for the treatment of PTCL in

P.L. Zinzani et al. / Critical Reviews in Oncology/Hematology 99 (2016) 214–227 217 OS,

year:

9.2 64%)

4 3

year:

Median 70%, NR 7.9 AITL: Not reached (1 NR Not reached NR NR 14.5 11.3 months year: 63%, lymphoma.

T-cell

5.8 6.7

Median PFS, months 12.9 1.4 1.6 20.0 10.8 2.6 PTCL-NOS: 1.6 AITL: NR 3.5 4 AITL: peripheral

CI) 7.6

29.4) 26.3)

4.2) DoR,

7.5 5.5

(4.5, (5.7, (6.6, (<1–22.1)

(1.8, (1.3–14+) (<1–48+)

Median 3.6 13.6 AITL: 13.2 9.7 12.3 7.6 PTCL-NOS: AITL: NR 10.1 28 months (range/95% 28.0+) (1.6–29.4) relapsed/refractory

(%) 0 19

14 14

regimens

rate

PTCL: ALCL:

18 38 19

and

−

CR/CRu 8 11 AITL: 59 80 63 24 PTCL-NOS: AITL: 31 11 15 PTCL-NOS: AITL: ALK Other agents

38 0 15 24 0

23 33 32 29

0 35

0 PTCL: PTCL: ALCL: ALCL:

46 54 8 30 ALCL:

(%)

− −

ORR PTCL-NOS: 25 26 AITL: ALK ALK+ EATL: ENKTCL: 86 100 88 41 PTCL-NOS: 54 29 PTCL-NOS: sALCL: AITL: tMF: 25 PTCL-NOS: AITL: ALK Other Other HSTCL: AITL: investigational/off-label

and

romidepsin) Central response review No Yes Yes Yes No No No Yes Yes

and

(1–9) (1–8) (1–6) (1–6) (2–6) (1–9) (1–12) (1–8)

pralatrexate,

Median prior therapies (range) 3 2 AITL: 2 3 3 2 NR 3 2 (1–5) vedotin,

10 13 13 21

1 13 177 22 59 69

= = = =

======

n n n n 1 2

n n n n n n 2

= =

58 5 8 17

brentuximab = 2 3 =

n n

= 3 22 13 13 27 = = = =

12 30

n = =

= = = = = n n n n n

PTCL PTCL

ALCL ALCL =

skin

ALCL

n n

diagnoses

n n n n n

− −

ENKTCL PTCL PTCL-NOS PTCL-NOS AITL sALCL sALCL sALCL PTCL-NOS TCL PTCL-NOS PTCL-NOS AITL SPTCL PTCL, NKTCL ALCL ALK+ Other HSTCL EATL Other tMF AITL ENKTCL ALK AITL AITL sALCL ALK (belinostat,

N 24 129 58 5 8 35 30 111 130 approved

for

trials

Phase 2 2 2 1/2 2 2 2/1/2 2 2 clinical

) ) ) )

)

) ) ) )

2015 2009 2011 )

) ) ) and 2013 2014a

2014 2012 2014

vedotin 2014a al., al., al.,

prospective

al., al., 2015

al., al., al.,

et et et

2012 2013 2014 of

al.,

et et

et et et

al.,

et al., al., al.,

et et et

reference Foss O’Connor Horwitz Pro Pro Pro Ogura Bartlett Horwitz O’Connor O’Connor Coifﬁer Coifﬁer Summary ( Table Agent/regimen Belinostat ( ( ( Brentuximab Romidepsin ( ( ( ( ( ( ( Pralatrexate ( (

218 P.L. Zinzani et al. / Critical Reviews in Oncology/Hematology 99 (2016) 214–227 OS,

Median NR NR NR NR 6.1 6.0 NR 8 months lymphoma.

T-cell

Median PFS, months NR NR NR NR 2.5 NR NR 3 peripheral

CI)

d DoR,

(2–74)

(2–10) (1–18)

Median 8.9 NR 7 NR NR NR NR 3 months (range/95% relapsed/refractory

(%)

19 43 8

tMF:

regimens 0

rate

0 25 0

subtypes 0

and

PTCL 7 CR/CRu 18 21 33 43 27 25 PTCL-NOS: NR 5 tMF: PTCL-NOS: AITL: ATLL: ALCL: excluding agents

100

41 PTCL-NOS: 86 31

tMF:

14 0 ENKTCL:

50 25 ALCL: 17 33

subtypes 0

(%)

−

ORR ALCL: ENKTCL: 38 AITL: 36 50 50 55 50 ENKTCL: 50 24 PTCL tMF: AITL: ATLL: excluding investigational/off-label

and

romidepsin) Central response review No No No No No No No No

and

(1–11) (1–4) (2–4) (1–6) (1–18)

pralatrexate,

Median prior therapies (range) 3 2 2 NR NR NR 3 vedotin,

n 9 21 ALK

2 2

27 10 63 3 4 7 13

= = =

= =

======

n n n 72 PTCL-NOS:

n n n n n n n

= =

3 2

brentuximab

1 2 8 4 PTCL-NOS: n n

72 5 PTCL-NOS: 1 9 = =

= 7

= = = =

= = = = = PTCL n n

ALCL ALCL = n

ALCL

n n diagnoses n n

n n n n n

− − lymphoma

Other T-PLL PTCL PTCL-NOS PTCL-NOS PTCL-NOS PTCL-NOS PTCL-NOS PTCL-NOS PTCL PTCL-NOS Angio-TCL ALK NK ALCL ALK Other ATLL ENKTCL tMF ALK+ AITL ALCL AITL AITL T-ALL AITL ENKTCL AITL (belinostat,

N 47 14 6 16 11 16 8 37 approved

for

trials

Phase 2 2 2 2 2 2 2 clinical

)

)2 ) )

2014 ) )

pentostatin FCD DHAP

and 2009

al., monotherapy

2005 2011 + + +

2004

al.,

prospective et

al., 2015

2009 al., al., et

al.,

et et et

al., al.,

) et et

2010 reference Piekarz Enblad Zinzani Ravandi Weidmann Kim Friedberg Barr ( ( ( ( Summary Agent/regimen ( Alisertib ( Alemtuzumab Alemtuzumab Alemtuzumab ( Alemtuzumab (

P.L. Zinzani et al. / Critical Reviews in Oncology/Hematology 99 (2016) 214–227 219 g e year: l

Not reached 73%) 6.3 NR NR (3 NR NR 8.4 NR 12 NR NR 4.6

4 g

e m

year:

i l 62%) 3.6 NR NR Not reached (3 NR 6 NR NR 4 R/R: NR 2.5 AITL: non-AITL: 1.9

l e

7.6)

(2–37+)

3.5

(1–21) (2.8, (11–19) (2–37+) (2–37)

3.5 NR NR 10 NR NR NR NR 13 R/R: NR 3.6 AITL: 21 0

: 15 −

e h i k

28 27 78 100 36 22 CD25+: CD25 PTCL-NOS: 13 11 PTCL-NOS: 8 30 11 AITL:

42 0 43 20

: modiﬁed

10 ALCL: 33 31

−

− on

i l m e h

ALK schedule) 50 36 (50 89 100 60 48 CD25+: CD25 PTCL-NOS: 47 11 PTCL-NOS: 26 R/R: ALCL: AITL: PTCL-NOS: 30 22 AITL: PTCL-NOS: ALCL:

−

No No Yes NR NR No No No ALK No No No 33 i j m f h k

l (1–6)

(1–3) (2–5) (1–6) (1–11) (1–8) (0–5) (2–7) (1–11)

1 3 NR NR 2 NR 4 2 1 4 3

TCL

2 2 3

9 9 14

23 12 19 6 14 10 20

= = =

======

n n n 1

n n n

n n n n n n n 1 1 2

3 1) 2)

= 2 10 16 = =

32 1 3 9 26 = = =

n = = = n n

= = = = = n

n PTCL n

ALCL ALCL =

ALCL ALCL ALCL

( n ( n n

n n n n n

− − 2

AITL EATL AITL PTCL-NOS PTCL-NOS ALK+ ALK+ ALK+ PTCL-NOS PTCL PTCL-NOS PTCL-NOS PTCL-NOS AITL n ALCL tMF HSTCL HSTCL EATL NKTCL Lymphoblastic ENKTCL Other ALK ALCL AITL AITL ALK PTCL-NOS sALCL l

58 16 9 9 14 27 16 9 39 10 50

b 1 2 2 1/2 1 2 2 1 1 2 2

)

) )

) ) ) )

al., )

) et 2014b 2013

al.,

2011

monotherapy

2013

2013 gemcitabine 2010 2012

2013

)

et 2007 al., + al.,

(BCX1777) diftitox

al.,

al., al., al., (IPI-145) al.,

al.,

et study

al.,

2013 et et et et

) )

al.,

2013 2015 et Damaj Evens Mossé Redaelli Gambacorti-Passerini Dang Horwitz Ogura Dueck Toumishey Zinzani Morschhauser ( ( Bendamustine ( ( ( ( ( ( ( ( Bortezomib Crizotinib ( Duvelisib BreakTable Pediatric Denileukin Forodesine ( Lenalidomide

220 P.L. Zinzani et al. / Critical Reviews in Oncology/Hematology 99 (2016) 214–227 OS, killer/T-

Median 6.7 NR 13.7 14.2 NR NR 10.2 months prolymphocytic sALCL—systemic

cALCL—cutaneous

lymphoma.

NKTCL—natural

T-cell

lymphoma;

T-PLL—T-cell

EATL—enteropathy-associated

Median PFS, months 2.2 1.5 5.2 2.0 2.1 NR 1.6 T-cell

fungoides;

peripheral

leukemia/lymphoma; response; fungoides;

CI)

T-cell

DoR, MF—mycosis

mycosis

PTCL—peripheral

(0–27.9) o

Median NR NR NR NR 2.9 NR 2.2 months (range/95% relapsed/refractory

DoR—duration

in ATLL—adult

lymphoma;

survival;

(%)

T-cell

tMF—transformed regimens

lymphoma;

rate

lymphoma; 15 ALCL:

and

− n B-cell

T-cell 100 CR/CRu 13 13 31 17 AITL: ALK 3 22 6

leukemia;

agents

large

PFS—progression-free

HSTCL—hepatosplenic

100

survival;

19 PTCL-NOS:

lymphoblastic

DLBCL—diffuse

31 ATLL: ALCL: 50

(%)

acute −

doxorubicin; TCL.

Angio-TCL—angiocentric

ORR 25 31 50 34 AITL: ALK 11 43 21 OS—overall

investigational/off-label

and

cytarabine;

and rate;

kinase;

and

T-ALL—T-cell

lymphoblastic

response

cisplatin, romidepsin) with

Central response review Yes No No

lymphoma

cyclophosphamide, and lymphoma;

patients

ORR—overall

and (1–2) No (1–3+) Yes (1–3) Yes

TCL—T-cell

(1–5) (1–8) (1–4) No (1–5) ALK—anaplastic

pralatrexate,

Median prior therapies (range) 2 2 2 reported;

cALCL. cALCL.

FCD—ﬂudarabine,

DLBCL.

MF. DHAP—dexamethasone,

vedotin, with

with

syndrome; type; with

CR; 2

NR—not

with lymphoma;

chemotherapy

16 1

DLBCL.

DLBCL. and

and

38 27 NR nasal SS.

2 cell +

1 1

= =

2 2 1611 17 PTCL-NOS:

and

= = = and

n n = = = = =

n ALK+ n n 2 3 MF,

n n n n n ALK CTCL, with speciﬁed;

= =

MF.

SS—Sézary 1

large

brentuximab 5 13 ATLL: n n

= 5NR 12 82 9

CTCL. = = ATLL PTCL

= = = =

with with ALCL

ALCL ALCL

MF.

ALCL

n diagnoses n combination

with with n n n n

1 with

− and

−

− lymphoma,

2 2

CCR4+: NR subtypes)

PTCL-NOS, for with

CRu—unconﬁrmed

with and

ALK ALK ENKTCL PTCL AITL All CCR4+ CCR4+: CCR4+ AITL PTCL-NOS ALK+ SPTCL ENKTCL ALCL ALK PTCL-NOS AITL PTCL-NOS ATLL PTCL-NOS PTCL-NOS AITL

otherwise

and 17 2

and

speciﬁed). lymphoma; (belinostat,

with

2 ALCL (various subtypes and and subtypes,

eligible

not ALCL

subtypes,

killer/T-cell ALCL—anaplastic

response;

T-cell

not NOS—not N 8 15 27 29 38 25 34

PTCL ALK+ PTCL PTCL ATLL, PTCL PTCL

ALK+ PTCL PTCL-NOS

approved

natural with with with with with with with

for

with with with (diagnoses

patients

16 9 14 26 16 9 50 13 6 58

lymphoma;

trials disease.

CR—complete CTCL

Phase 1 2 2 2 extravascular); panniculitis-like

T-cell

or with patients: patients: patients: patients: patients: patients: patients: patients: patients: patients:

untreated retreatment. stable

clinical

of 10 60 32 11 15 27 33 13 54 16

) 1/2 type

lymphoma; for for for for for for for for for for ) )

) )2 ENKTCL—extranodal patients

vedotin 2014

)2 cell and

vorinostat/dexamethasone (nasal

bortezomib al.,

previously

2014

+ duration al., 2013

2014b 2012

8 prospective

progression.

et 2014 al.,

large al., of

al., al.,

presented presented presented presented presented presented presented presented presented presented

includes et

al., et et

)

SPTCL—subcutaneous lymphoma;

Time Brentuximab Also Data Data Data Data Data Data Data Data Includes Data Data Including lymphoma

l i j f 2010 reference c a e g k o b d h n m Hopﬁnger Yamamoto Ishida Ogura Zinzani Goh Ribrag Summary Agent/regimen Lenalidomide AITL—angioimmunoblastic ( ( Mogamulizumab ( Plitidepsin ( ( ( ( Panobinostat T-cell ALCL; cell anaplastic leukemia.

P.L. Zinzani et al. / Critical Reviews in Oncology/Hematology 99 (2016) 214–227 221

patients who have received at least one prior therapy (ISTODAX , et al., 2014). Electrocardiographic changes have also been reported

2015). The third approved drug is belinostat, another potent IV during romidepsin treatment, although these do not appear to be

(class 1/2/4), epigenetic-modifying HDAC inhibitor (O’Connor et al., clinically relevant for patients without pre-existing cardiac abnor-

® ®

2015; BELEODAQ , 2015; Bodiford et al., 2014; Poole, 2014), which malities (ISTODAX , 2015; Foss et al., 2014). Belinostat treatment

is indicated for the treatment of patients with relapsed or refractory resulted in response rates of a similar magnitude to those seen with

PTCL (BELEODAQ , 2015). The ﬁnal approved agent is brentux- pralatrexate and romidepsin in the pivotal phase 2 BELIEF study of

≥

imab vedotin, an antibody-drug conjugate (ADC) directed against 129 patients with relapsed/refractory PTCL after failure of 1 prior

CD30, a cell-surface antigen that is selectively expressed by malig- systemic therapy (ORR 26%, CR rate 11%) (O’Connor et al., 2015).

nant cells, particularly in sALCL and variably in other TCL subtypes Furthermore, prolonged responses were observed in some patients

(Karube et al., 2008; Chen et al., 2013). Brentuximab vedotin was (median duration, 13.6 months; maximum duration, >36 months).

granted accelerated approval in the United States for the treatment Median PFS and OS were 1.6 and 7.9 months, respectively. A sub-

of sALCL after failure of at least one multiagent chemotherapy reg- group analysis suggested that belinostat may have particularly high

imen (ADCETRIS , 2015a), and is also approved in the European activity in patients with pathologically conﬁrmed AITL (ORR 46%;

Union for the treatment of adult patients with relapsed or refrac- n = 22) (O’Connor et al., 2015; Horwitz et al., 2013). Because the

tory sALCL (ADCETRIS , 2015b). European approvals of pralatrexate drug appears to have a favorable safety proﬁle, including a low risk

and romidepsin were both rejected on the grounds of lack of evi- of grade 3/4 hematologic AEs (O’Connor et al., 2015), belinostat

dence of clinical beneﬁt. Belinostat is not licensed in Europe, but has may have potential in combination regimens, and may also be suit-

been granted orphan designation status by the European Medicines able for patients with pre-existing thrombocytopenia or anemia (as

Agency. suggested in a recent subanalysis of the BELIEF data (Savage et al.,

As would be expected from their indications, pralatrexate, 2014).

romidepsin, and belinostat were approved in the United States Overall, these results suggest that pralatrexate, romidepsin, and

based on their activity in mixed populations of patients with PTCL belinostat have similar activity to each other across a range of

(Table 1) (Foss et al., 2015; O’Connor et al., 2009, 2011, 2015; Coifﬁer PTCL subtypes; however, current data indicates that pralatrexate

et al., 2012, 2014; Piekarz et al., 2011). Approvals were based on should not be used to treat AITL (at least until further studies

response rates alone, as none of these agents has yet been shown are conducted) due to lack of efﬁcacy, belinostat may be partic-

to improve OS. Importantly, all three drugs were generally well tol- ularly active in AITL (an observation that requires conﬁrmation),

erated with no cumulative toxicity, and negligible impact on quality and romidepsin may not be as active in patients with the rarest

of life. PTCL subtypes. As preclinical data suggest the potential for syn-

Response rates reported for pralatrexate in the pivotal phase ergy between romidepsin and pralatrexate (Jain et al., 2012), it

2 PROPEL trial (N = 115) were fairly consistent across different seems appropriate to investigate these two agents in combination

relapsed/refractory PTCL subtypes (ORR 25–38%; combined ORR in future studies in relapsed/refractory PTCL, and an investigator-

29%, including 12 CRs), except AITL, where the ORR was much lower initiated phase 1/2 study is already underway (NCT01947140).

(8%) (Table 1) (O’Connor et al., 2011). The authors of the study sug- These agents also have the potential to act as a bridge to SCT.

gested that the lower response rates in AITL patients may reﬂect The remaining approved agent, brentuximab vedotin, an ADC,

the unique biology of the condition or may simply be an artifact comprises an anti-CD30 chimeric antibody (cAC10) conjugated

due to the small sample size. Among patients who received only to the microtubule-disrupting agent, monomethyl auristatin E

one prior systemic treatment, the ORR was 35% (O’Connor et al., (MMAE) (Chen et al., 2013). Once brentuximab vedotin binds to

2011), suggesting that the response rate might be higher if prala- CD30, the ADC—receptor complex is internalized and MMAE is

trexate is used early on during therapy (i.e., second line). In primary released by proteolytic cleavage. Binding of MMAE to tubulin dis-

refractory patients, the ORR was 19%, indicating the potential to rupts the microtubule network within the cell, inducing cell-cycle

overcome resistance. Median PFS and OS were 3.5 and 14.5 months, arrest and apoptosis. After observing a CR to brentuximab vedotin

respectively. Although efﬁcacious, the toxicity of pralatrexate can in 2/2 patients with sALCL in a phase 1 study of 45 patients with

be signiﬁcant, especially oral mucositis (which occurred despite relapsed or refractory CD30-positive lymphomas (predominantly

supplementation with vitamin B12 and folic acid), immunosup- Hodgkin lymphoma [HL]) (Younes et al., 2010), a dedicated, piv-

pression, and thrombocytopenia (Shimanovsky and Dasanu, 2013). otal, phase 2 single-arm study was conducted to evaluate the

As such, pralatrexate may be unsuitable for certain patients, includ- efﬁcacy and safety of the drug in 58 patients with sALCL who had

ing the frail and those with signiﬁcant comorbidities. relapsed after prior therapy (Table 1) (Pro et al., 2012). Despite

In the pivotal trial of romidepsin in relapsed/refractory PTCL the fact the 62% of patients were primary refractory, treatment

(N = 130), response rates were similar among patients with PTCL- with brentuximab vedotin was associated with an 86% ORR by

NOS (ORR 29%, CR rate 14%), AITL (ORR 30%, CR rate 19%), and independent review (median duration, 12.6 months), with 57% of

−

ALK ALCL (ORR 24%, CR rate 19%), but no responses were seen patients achieving a CR (median duration, 13.2 months). At the 4-

in patients with rarer PTCL subtypes (Coifﬁer et al., 2012); again, year follow-up, median PFS among all patients was 20 months and

≥

the lack of efﬁcacy in rare PTCL entities could be an anomaly 4-year OS was 64% (Pro et al., 2014). The most frequent ( 20%)

due to the limited number of patients. A recent study update AEs were peripheral sensory neuropathy, nausea, fatigue, pyrexia,

reported that PTCL patients who responded to romidepsin could diarrhea, rash, constipation, and neutropenia. Results from these

achieve durable responses (median duration, 28 months after 22.3 phase 2 trials led to the regulatory approvals for the treatment of

months median follow-up; range, <1–48+ months) (Coifﬁer et al., relapsed/refractory sALCL, and established brentuximab vedotin as

2014). Median PFS and OS at this assessment were 4 and 11.3 the treatment of choice for this condition, with response rates that

months, respectively. Like other HDAC inhibitors, side effects asso- are currently unsurpassed.

ciated with romidepsin are predominantly hematologic in nature Following on from this trial, new data from a phase 2 study of

and include neutropenia, lymphopenia, thrombocytopenia, and 29 patients with HL (n = 21) or sALCL (n = 8) suggest that retreat-

anemia (Khot et al., 2013a; ISTODAX , 2015; Foss et al., 2014). ment with single-agent brentuximab vedotin (following relapse

Other side effects include infections (some of which may be seri- after achieving a CR or partial response [PR] during prior bren-

ous), fatigue/asthenia, nausea/vomiting, and other gastrointestinal tuximab vedotin therapy) can also result in high response rates in

adverse events (AEs) (Khot et al., 2013a; ISTODAX , 2015; Foss sALCL patients (ORR 88%, CR rate 63%, median duration of response

12.3 months) similar to those seen during initial treatment (Bartlett

222 P.L. Zinzani et al. / Critical Reviews in Oncology/Hematology 99 (2016) 214–227

et al., 2014). This illustrates the feasibility of brentuximab vedotin PTCL-NOS, respectively), the lack of durability of response (median

retreatment in sALCL, and shows that similar high response rates duration, 3.5 months across all PTCL and CTCL subtypes) suggests

may be achieved on the second or third applications. that bendamustine is more likely to be investigated in the future as

In addition to therapeutic antibodies, small molecule drugs may a component of combination regimens (Damaj et al., 2013). How-

also have a role in the future treatment of relapsed/refractory PTCL. ever, the short duration of response may reﬂect the fact that nearly

Crizotinib, for example, is a small molecule, oral tyrosine kinase half of the patients (45%) were refractory to their last treatment.

inhibitor of ALK and c-ros oncogene 1 (ROS-1) that is approved Median PFS and OS were 3.6 and 6.3 months, respectively. Grade

for use in ALK+ metastatic non-small cell lung cancer (Mossé 3/4 AEs associated with bendamustine were typical of alkylating

et al., 2013; Redaelli et al., 2013; Gambacorti-Passerini et al., 2011, chemotherapies, and included hematologic toxicities, infections,

2013; XALKORI , 2015). In small-scale, mixed population stud- skin reactions, mucositis, and arrhythmia (Damaj et al., 2013).

ies, crizotinib has been shown to exert high and durable activity Clinical data are also available for the oral purine nucleoside

in previously treated ALK+ sALCL patients (ORR 60–100%, CR rate phosphorylase (PNP) inhibitor, forodesine (BCX1777) (Ogura et al.,

38–100%), while exhibiting a relatively benign safety proﬁle (Mossé 2012). This compound is of interest as PNP is an important catalytic

et al., 2013; Redaelli et al., 2013; Gambacorti-Passerini et al., 2011, enzyme in the purine salvage pathway, and its deﬁciency is associ-

2013). AEs associated with crizotinib, most of which are mild or ated with T-cell lymphopenia (Al-Kali et al., 2010). In a small phase

moderate, include diarrhea, nausea/vomiting, visual disturbances, 1 trial, forodesine treatment led to a durable CR (PFS 331 days)

asthenia/fatigue, cough, neutropenia, and liver enzyme elevations in one patient with ALK− sALCL (Ogura et al., 2012). However, no

(Mossé et al., 2013; Gambacorti-Passerini et al., 2013). Larger stud- additional objective responses were seen in the remaining eight

ies are now needed to conﬁrm these initial ﬁndings. patients with PTCL (six with PTCL-NOS and two with ALK− sALCL).

Treatment was generally well tolerated, apart from a high rate of

3.3. Investigational and off-label therapies in relapsed/refractory grade 3/4 lymphopenia. Although forodesine is still under active

PTCL investigation in relapsed/refractory PTCL in Japan (NCT01776411),

its clinical development appears to have been discontinued by the

In addition to these approved drugs, a number of novel ther- manufacturer in other regions.

apeutic agents and regimens in various drug classes are under Given the activity of romidepsin and belinostat in

investigation in relapsed/refractory PTCL, mainly in studies of relapsed/refractory PTCL, it is unsurprising that the oral pan-

patients with mixed PTCL diagnoses. Some of these drugs are HDAC (class 1/2/4) inhibitor, panobinostat, is under evaluation in

already approved for use in other hematologic malignancies this setting (Goh et al., 2014; Anne et al., 2013). This experimental

or solid tumors, while others are purely experimental. These drug is also in clinical development in various lymphoid and

investigational agents include alisertib, bendamustine, forodesine, myeloid malignancies (including CTCL and multiple myeloma, for

panobinostat, bortezomib, denileukin diftitox, lenalidomide, alem- which it has recently been approved in the United States (National

tuzumab, mogamulizumab, crizotinib, duvelisib, plitidepsin, and Cancer Institute, 2015b), and solid tumors (Anne et al., 2013; Khot

selinexor. Available efﬁcacy data on all of these agents are summa- et al., 2013b)). In PTCL, panobinostat was assessed in combination

rized in Table 1. with the proteasome inhibitor, bortezomib, in a small phase 2

Alisertib (MLN8237) is an experimental, orally administered, study involving 25 patients with refractory PTCL after the failure of

selective inhibitor of aurora A kinase (a serine-threonine protein conventional chemotherapy (Goh et al., 2014). The ORR achieved

kinase expressed on all rapidly dividing cells that regulates mitotic with this combination was 43%, including a 22% CR rate, and

spindle formation and centrosome maturation/separation during treatment was generally well tolerated (Goh et al., 2014). Drug-

mitosis) that is being developed for the treatment of a range of related grade 3/4 AEs included thrombocytopenia, neutropenia,

hematologic malignancies and solid tumors (Friedberg et al., 2014; diarrhea, and asthenia/fatigue. The study investigators suggest

Barr et al., 2015; Manfredi et al., 2011). Following demonstration that panobinostat/bortezomib may serve as a bridge to allo-SCT for

of promising single-agent activity across a range of PTCL entities eligible patients who have failed other treatments. In this trial, ﬁve

(including an ORR of 30% in patients with various PTCL subtypes) of the 25 treated patients underwent successful transplantation

(Friedberg et al., 2014; Barr et al., 2015), a randomized, open- (Goh et al., 2014).

label phase 3 trial has been initiated to compare the efﬁcacy and The ﬁrst-generation IV proteasome inhibitor, bortezomib, a

safety of single-agent alisertib versus the investigator’s choice of drug widely used in multiple myeloma and pretreated mantle cell

treatment (pralatrexate, gemcitabine, or romidepsin) in patients lymphoma (National Cancer Institute, 2015a,b), has also been com-

with relapsed/refractory PTCL (NCT01482962). The primary results bined with gemcitabine in a phase 1/2 trial of patients with relapsed

from this trial are expected in late 2016. Phase 1 data in mixed or refractory PTCL or diffuse large B-cell lymphoma (DLBCL) (Evens

relapsed/refractory lymphoma subtypes also suggest the poten- et al., 2013). An ORR of 36% (CR rate 27%) was observed in 16 PTCL

tial of combining alisertib with HDAC inhibitors (vorinostat or patients treated with bortezomib/gemcitabine (Evens et al., 2013).

romidepsin) (Siddiqi et al., 2014; Fanale et al., 2014). So far, com- Among six PTCL patients who received a schedule that was modi-

bination treatment appears tolerable (Siddiqi et al., 2014; Fanale ﬁed to improve hematologic tolerability, the ORR was an impressive

et al., 2014), and one of three PTCL patients treated with alis- 50%. Though patient numbers were small, the modiﬁed schedule

ertib/romidepsin has achieved a CR lasting 5+ months (Fanale et al., appeared to be reasonably well tolerated with a low incidence of

2014). Common grade 3/4 alisertib-related AEs include hemato- grade 3/4 hematologic AEs.

logic toxicities, stomatitis/mucositis, and rash; these AEs tend to The interleukin-2 (IL-2)–diphtheria toxin fusion protein,

manageable and reversible (Friedberg et al., 2014; Barr et al., 2015). denileukin diftitox is an approved treatment for patients with per-

The alkylating, nitrogen mustard chemotherapeutic drug, ben- sistent or recurrent CTCL whose cells express the CD25 component

damustine – which is used in the United States to treat chronic of the IL-2 receptor (ONTAK , 2014). In a small phase 2 trial of 27

lymphocytic leukemia and indolent B-cell NHL (TREANDA , 2015) patients with relapsed/refractory PTCL, denileukin diftitox treat-

– has been evaluated in a phase 2 trial of 60 patients with ment was associated with high response rates (ORR 48%, CR rate

relapsed/refractory PTCL or CTCL who had progressed after receiv- 22%), particularly among patients with CD25+ lymphomas (ORR

ing one or more lines of prior chemotherapy (Damaj et al., 2013). 62%) (Dang et al., 2007). This led to further development of this

While high response rates were attained across multiple PTCL sub- unique agent in the frontline setting, where impressive results have

types (including ORRs of 69% and 41% in patients with AITL and been shown for denileukin diftitox when combined with CHOP

P.L. Zinzani et al. / Critical Reviews in Oncology/Hematology 99 (2016) 214–227 223

(Foss et al., 2013). However, supply of denileukin diftitox for general tuzumab is approved to treat B-cell chronic lymphocytic leukemia,

use has been on hold since 2011 (with product discontinuation in it is no longer available commercially in the United States, and can

2014) due to the risk of serious toxicities (capillary leak syndrome, only be obtained via a distribution program. This is because the

infusion reactions, and visual loss (ONTAK , 2014)). While further therapeutic antibody is linked with an increased risk of serious and

development of denileukin diftitox per se is unlikely to be pursued sometimes fatal cytopenias, infusion reactions, and opportunis-

in PTCL, clinical trials of an improved purity formulation (E7777) tic infections (Campath , 2015). It is also no longer authorized in

are ongoing in previously treated CTCL (Duvic et al., 2014) and Europe.

PTCL (NCT01401530). It is too early to say whether this improved Another therapeutic antibody under investigation in

formulation will result in a better tolerability proﬁle. relapsed/refractory PTCL is the defucosylated, humanized, mon-

Another toxic compound, plitidepsin – an investigational cyto- oclonal antibody, mogamulizumab (KY-0761), that targets CC

toxic cyclodepsipeptide originally isolated from the Mediterranean chemokine receptor 4 (CCR4), a marker for type 2 helper T cells

tunicate Aplidium albicans – has demonstrated signs of anti- or regulatory T (Treg) cells that is variably expressed in most

lymphoma activity (ORR 21%, including two CRs) in 29 patients PTCLs, but widely expressed in ATLL (Yamamoto et al., 2010; Ishida

with non-cutaneous PTCL participating in a phase 2 trial in mixed et al., 2012; Ogura et al., 2014b). Mogamulizumab demonstrated

relapsed/refractory, aggressive NHL (Ribrag et al., 2013). It is not particularly high activity in Japanese patients with previously

known, however, whether development of plitidepsin in PTCL will treated, relapsed CCR4+ ATLL (ORR 50%, CR rate 31%, median PFS

be pursued, as no clinical trials are ongoing or planned for this 5.2 months, median OS 13.7 months) without many of the serious

indication. autoimmune side effects associated with alemtuzumab (Ishida

The orally administered, immunomodulatory, synthetic thalido- et al., 2012). Based on these data, mogamulizumab was approved

mide derivative, lenalidomide, which is widely used to treat for the treatment of relapsed or refractory ATLL in Japan in 2012

multiple myeloma and mantle cell lymphoma (REVLIMID , 2015), (Subramaniam et al., 2012). This indication was subsequently

has been investigated in several studies in relapsed/refractory PTCL extended in 2014 to include previously treated patients with PTCL

(Dueck et al., 2010; Toumishey et al., 2015; Zinzani et al., 2011; or CTCL based on the results of a phase 2 Japanese trial, which

Morschhauser et al., 2013). As monotherapy, this drug has achieved reported an ORR of 35% (34% in PTCL) and CR rate of 14% in patients

responses in heavily pretreated PTCL patients (ORR 22–30%, CR rate who had relapsed after their last systemic therapy (Ogura et al.,

8–30%), particularly those with AITL, sALCL, or PTCL-NOS, and has 2014b). For European and United States regulatory purposes, a

a predictable AE proﬁle (common grade 3/4 AEs included hema- randomized controlled phase 3 trial is currently investigating

tologic, gastrointestinal, and constitutional toxicities) (Toumishey the efﬁcacy and safety of mogamulizumab versus investigator’s

et al., 2015; Zinzani et al., 2011; Morschhauser et al., 2013). These choice of treatment (pralatrexate; gemcitabine plus oxaliplatin;

response rates and other efﬁcacy measures, including PFS and OS, or dexamethasone, cisplatin, and cytarabine) in patients with

are very similar to those reported for single-agent romidepsin, previously treated ATLL, excluding smoldering type, who have

belinostat, and pralatrexate in relapsed/refractory PTCL (Table 1). relapsed or are refractory after at least 1 prior systemic therapy

However, the beneﬁts of lenalidomide must be weighed up against (Phillips et al., 2014). Interestingly, a recent phase 2 trial of

the potential risks of serious AEs, such as embryo-fetal toxic- mogamulizumab in 38 European patients with relapsed/refractory

ity, thromboembolism, allergic reactions, tumor lysis syndrome, CCR4+ PTCL only reported an ORR of 11% (Zinzani et al., 2014),

and tumor ﬂare reaction, as observed in other malignancies which is much lower than that reported in Japanese patients

(REVLIMID , 2015). As well as in monotherapy, lenalidomide may (Ogura et al., 2014b). The study investigators attributed the low

also form a component of combination regimens. Disappointingly, response rate to the inclusion of a high proportion of refractory

a small phase 1/2 study of 8 patients with relapsed/refractory patients (49%), and differences in performance status and response

PTCL reported no additional beneﬁt (ORR 25%, median PFS 2.2 assessment. Median PFS was, nevertheless, similar in the two

months, median OS 6.7 months), compared with published reports trials. Mogamulizumab-related AEs, which are mainly low grade,

for monotherapy, when lenalidomide was combined with vorinos- include infusion reactions, hematologic toxicities, fever, chills,

tat (an oral HDAC inhibitor approved for use in relapsed/refractory nausea, skin disorders, and liver transaminase elevations (Ishida

CTCL (ZOLINZA , 2015) and dexamethasone (Hopﬁnger et al., et al., 2012; Ogura et al., 2014b; Zinzani et al., 2014).

2014). This ﬁnding was, however, attributed to the poor tolerabil- In addition to therapeutic antibodies, small molecule drugs may

ity of the regimen, which restricted the dose of lenalidomide to a also have a role in the future treatment of relapsed/refractory

maximum of 5 mg/day. The approved dose of lenalidomide in other PTCL. Crizotinib, for example, is a small molecule, oral tyrosine

hematologic malignancies is 25 mg/day (REVLIMID , 2015). kinase inhibitor of ALK and c-ros oncogene 1 (ROS-1) that is

It is likely that future regimens in relapsed/refractory PTCL will approved for use in ALK+ metastatic non-small cell lung cancer

feature target-speciﬁc monoclonal antibodies that act, amongst (Mossé et al., 2013; Redaelli et al., 2013; Gambacorti-Passerini

other ways, to promote antibody-dependent cellular toxicity and et al., 2011,2013; XALKORI , 2015). In small-scale, mixed popu-

apoptosis in malignant T-cells (Ogura et al., 2014a; Zinzani et al., lation studies, crizotinib has been shown to exert high and durable

2012). In this regard, the humanized, anti-CD52 monoclonal activity in previously treated ALK+ sALCL patients (ORR 60–100%,

antibody, alemtuzumab, has been evaluated clinically both as CR rate 38–100%), while exhibiting a relatively benign safety pro-

monotherapy and in combination with chemotherapy (FCD, DHAP, ﬁle (Mossé et al., 2013; Redaelli et al., 2013; Gambacorti-Passerini

or pentostatin) (Enblad et al., 2004; Zinzani et al., 2005; Ravandi et al., 2011, 2013). AEs associated with crizotinib, most of which are

et al., 2009; Weidmann et al., 2010; Kim et al., 2009). This antibody mild or moderate, include diarrhea, nausea/vomiting, visual dis-

targets the CD52 cell-surface glycoprotein antigen of unknown turbances, asthenia/fatigue, cough, neutropenia, and liver enzyme

function expressed on T cells, B cells, and some other immune cells elevations (Mossé et al., 2013; Gambacorti-Passerini et al., 2013).

(Zinzani et al., 2012). Despite showing encouraging single-agent Larger studies are now needed to conﬁrm these initial ﬁndings.

and combined activity in relapsed/refractory PTCL (ORR 36–55%) Another small molecule oral drug, duvelisib (IPI-145), which

(Enblad et al., 2004; Zinzani et al., 2005; Ravandi et al., 2009; inhibits phosphoinositide-3-kinases ␦ and ␥ (important enzymes

Weidmann et al., 2010; Kim et al., 2009), recent research on alem- preferentially expressed by leukocytes, which are involved in reg-

tuzumab has predominantly focused on ﬁrst-line treatment, where ulating malignant T-cell growth and survival (Horwitz et al., 2014b;

it is has been combined with CHOP, ESHAP, and dose-adjusted Winkler et al., 2013), may have utility in previously treated PTCL

EPOCH (Zinzani et al., 2012). It should be noted that while alem- (Horwitz et al., 2014b). Data from a disease-speciﬁc cohort of

224 P.L. Zinzani et al. / Critical Reviews in Oncology/Hematology 99 (2016) 214–227

patients with relapsed/refractory PTCL or CTCL participating in Conﬂicts of interest: P.L.Z., S.P. advisory board membership

an ongoing phase 1 study showed that duvelisib treatment could (Takeda).

achieve an ORR of 47% (including two CRs) in 15 evaluable PTCL

patients (Horwitz et al., 2014b). Median OS in PTCL patients was Funding

36.4 weeks and the most common grade 3/4 AEs among all patients

were elevated liver transaminases, rash, and neutropenia. Based on

The development of this publication was funded by Millen-

these data, duvelisib appears to be highly active in PTCL and further

nium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda

study is justiﬁed.

Pharmaceutical Company Ltd. Vijayveer Bonthapally, Dirk Hueb-

Finally, the oral selective inhibitor of nuclear export (SINE),

ner, Richard Lutes, and Andy Chi are employed by Millennium.

selinexor (KPT-330), may be active in relapsed/refractory PTCL

(Kuruvilla et al., 2014). This XPO1 (Exportin-1/Chromosome Region

Acknowledgments

Maintenance 1/CRM1) antagonist acts to block nucleo-cytoplasmic

transport of nuclear proteins in malignant cells, thereby facilitat-

The authors would like to acknowledge the writing assistance

ing apoptosis (Kuruvilla et al., 2014; Gravina et al., 2014). Based on

of Duncan Campbell of FireKite, an Ashﬁeld Company, part of UDG

early signs of activity in TCL (CR in 1/5 patients) in a phase 1 trial

Healthcare plc, during the development of this publication, which

of a mixed population of 58 patients with relapsed/refractory NHL

was funded by Millennium Pharmaceuticals Inc., a wholly owned

(Kuruvilla et al., 2014), a multicenter phase 2 trial in relapsed or

subsidiary of Takeda Pharmaceutical Company Ltd, and complied

refractory PTCL or CTCL patients is planned (NCT02314247). Treat-

with Good Publication Practice 3 ethical guidelines (Battisti WP,

ment with selinexor appears to be generally well tolerated when

et al. Ann Intern Med 2015;163:461–4.) All authors were involved

supportive care measures are instigated; toxicities include hema-

in drafting the article or revising it critically for important intellec-

tologic AEs, fatigue, nausea/vomiting, and anorexia (Kuruvilla et al.,

tual content, and have approved the ﬁnal draft for submission. 2014).

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Biography

etoposide (ICE)-based second-line chemotherapy for the management of

relapsed and refractory aggressive non-Hodgkin’s lymphoma. Ann. Oncol. 14,

i5–10, http://dx.doi.org/10.1093/annonc/mdg702.

Pier Luigi Zinzani is an Associate Professor of Hematology at the Institute of

Zinzani, P.L., Magagnoli, M., Bendandi, M., et al., 1998. Therapy with gemcitabine in

pretreated peripheral T-cell lymphoma patients. Ann. Oncol. 9 (12), Hematology ‘L. e A. Seràgnoli’ at the University of Bologna in Italy. He is a member

1351–1353. of the Italian Society of Hematology, Italian Society of Experimental Hematology,

Zinzani, P.L., Baliva, G., Magagnoli, M., et al., 2000. Gemcitabine treatment in American Society of Hematology, and American Society of Clinical Oncology, and is

pretreated cutaneous T-cell lymphoma: experience in 44 patients. J. Clin. currently serving as President of the Fondazione Italiana Linfomi. Professor Zinzani

Oncol. 18 (13), 2603–2606.

has presented his research at more than 220 national and international congresses,

Zinzani, P.L., Alinari, L., Tani, M., et al., 2005. Preliminary observations of a phase II

has written more than 400 peer-reviewed articles in high-proﬁle hematology and

study of reduced-dose alemtuzumab treatment in patients with pretreated

oncology journals, and has held the position of Associate Editor of Annals of Oncology

T-cell lymphoma. Haematologica 90 (5), 702–703.

since January 2014. His current research projects focus on clinical trial method-

Zinzani, P.L., Venturini, F., Stefoni, V., et al., 2010. Gemcitabine as single agent in

ology, new drug development, non-Hodgkin lymphoma (including exploration of

pretreated T-cell lymphoma patients: evaluation of the long-term outcome.

prognostic factors), Hodgkin’s disease, chronic lymphocytic leukemia, and hairy cell

Ann. Oncol. 21 (4), 860–863, http://dx.doi.org/10.1093/annonc/mdp508. leukemia.