Abstract

Peripheral T-cell lymphomas (PTCLs) are a heterogenous group of aggressive non-Hodgkin lymphomas that are less chemosensitive than their B-cell counterparts. Until recently, standard therapy did not distinguish between subtypes, and deeper understanding of the biology of these diseases was lacking. The availability of targeted therapy and more sophisticated subtype classification has translated into the development of novel treatment options for these rare diseases. This includes the development of a brentuximab vedotin-based upfront chemotherapy regimen that confers an overall survival benefit for a subset of patients. Clinical trials of targeted agents, as well as development of better preclinical models of PTCL, are leading to therapeutic advances in the field, including the development of phosphoinositide-3-kinase inhibitors, histone deacetylase inhibitor-based strategies, CD30-directed strategies, Janus kinase inhibitors, and spleen-associated tyrosine kinase inhibitors. Better understanding of the biology of these diseases based on gene expression profiling, minimal residual disease evaluation, and modeling in patient-derived xenografts should help define mechanisms of response and resistance to therapy. Given the complex biology of these heterogeneous lymphomas, well-tolerated combination strategies targeted toward specific subtypes of PTCL can lead to advances in the field. Similar to the story of brentuximab vedotin, development of effective therapies in the salvage setting will likely lead to improved upfront strategies in PTCLs, and ultimately a more personalized approach.

References

References
1.
Vose
J
,
Armitage
J
,
Weisenburger
D
;
International T-Cell Lymphoma Project
.
International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes
.
J Clin Oncol
.
2008
;
26
(
25
):
4124
-
4130
.
2.
Ellin
F
,
Landström
J
,
Jerkeman
M
,
Relander
T
.
Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry
.
Blood
.
2014
;
124
(
10
):
1570
-
1577
.
3.
d’Amore
F
,
Relander
T
,
Lauritzsen
GF
, et al
.
Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01
.
J Clin Oncol
.
2012
;
30
(
25
):
3093
-
3099
.
4.
Schmitz
N
,
Trümper
L
,
Ziepert
M
, et al
.
Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group
.
Blood
.
2010
;
116
(
18
):
3418
-
3425
.
5.
Advani
RH
,
Ansell
SM
,
Lechowicz
MJ
, et al
.
A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) Alternating with Pralatrexate (P) as front line therapy for patients with peripheral T-cell lymphoma (PTCL): final results from the T- cell consortium trial
.
Br J Haematol
.
2015
;
172
(
4
):
535
-
544
.
6.
Gleeson
M
,
Peckitt
C
,
To
YM
, et al
.
CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2, multicentre, randomised, open-label trial
.
Lancet Haematol
.
2018
;
5
(
5
):
e190
-
e200
.
7.
Lunning
M
,
Horwitz
S
,
Advani
R
, et al
.
Phase I/II study of CHOEP plus lenalidomide as initial therapy for patients with stage II-IV peripheral T-cell lymphoma: phase II results
.
Blood
.
2018
;
132
(
Suppl 1
):
2899
.
8.
Altman
B
,
Wulf
G
,
Truemper
L
, et al
.
Alemtuzumab added to CHOP for treatment of peripheral T-cell lymphoma (PTCL) in previously untreated young and elderly patients: pooled analysis of the international ACT-1/2 phase III trials
.
Blood
.
2018
;
132
(
Suppl 1
):
1622
.
9.
Horwitz
S
,
O’Connor
OA
,
Pro
B
, et al
;
ECHELON-2 Study Group
.
Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial
.
Lancet
.
2019
;
393
(
10168
):
229
-
240
.
10.
Mehta-Shah
N
,
Ito
K
,
Bantilan
K
, et al
.
Baseline and interim functional imaging with PET effectively risk stratifies patients with peripheral T-cell lymphoma
.
Blood Adv
.
2019
;
3
(
2
):
187
-
197
.
11.
Mehta-Shah
N
,
Reichel
J
,
Tang
J
, et al
.
Peripheral blood cell free DNA can identify tumor specific somatic mutations in angioimmunoblastic T-cell lymphoma
.
T-cell Lymphoma Forum; January 26-28
,
2017
;
San Francisco, CA
.
12.
Lansigan
F
,
Horwitz
SM
,
Pinter-Brown
LC
, et al
.
Differential outcome of patients with primary refractory vs. relapsed peripheral T-cell lymphoma: analysis from a prospective multicenter US cohort study
.
Blood
.
2016
;
128
(
22
):
4150
.
13.
Mehta-Shah
N
,
Teja
S
,
Tao
Y
, et al
.
Successful treatment of mature T-cell lymphoma with allogeneic stem cell transplantation: the largest multicenter retrospective analysis
.
Blood
.
2017
;
130
:
4597
.
14.
O’Connor
OA
,
Pro
B
,
Pinter-Brown
L
, et al
.
Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study
.
J Clin Oncol
.
2011
;
29
(
9
):
1182
-
1189
.
15.
O’Connor
OA
,
Horwitz
S
,
Masszi
T
, et al
.
Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study
.
J Clin Oncol
.
2015
;
33
(
23
):
2492
-
2499
.
16.
Pro
B
,
Advani
R
,
Brice
P
, et al
.
Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma
.
Blood
.
2017
;
130
(
25
):
2709
-
2717
.
17.
Foss
F
,
Horwitz
S
,
Pro
B
, et al
.
Romidepsin for the treatment of relapsed/refractory peripheral T cell lymphoma: prolonged stable disease provides clinical benefits for patients in the pivotal trial [published correction appears in J Hematol Oncol. 2017;10(1):154]
.
J Hematol Oncol
.
2016
;
9
(
1
):
22
.
18.
Wang
C
,
McKeithan
TW
,
Gong
Q
, et al
.
IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma
.
Blood
.
2015
;
126
(
15
):
1741
-
1752
.
19.
Schatz
JH
,
Horwitz
SM
,
Teruya-Feldstein
J
, et al
.
Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis
.
Leukemia
.
2015
;
29
(
1
):
237
-
241
.
20.
Ghione
P
,
Ozkaya
N
,
Faruque
P
,
Mehta-Shah
N
,
Lunning
MA
,
Ruan
J
.
Romidepsin activity in T follicular helper(TFH)-phenotype PTCL versus non TFH treated on the same clinical trials [abstract]
.
J Clin Oncol
.
2018
;
36
(
15
):
7509
.
21.
Mehta-Shah
N
,
Lunning
MA
,
Ruan
J
, et al
.
A phase I/II trial of the combination of romidepsin and lenalidomide in patients with relapsed/refractory lymphoma and myeloma
.
Hematol Oncol
.
2015
;
33
:
108
.
22.
Mehta-Shah
N
,
Moskowitz
A
,
Lunning
M
, et al
.
A phase Ib/IIa trial of the combination of romidepsin, lenalidomide and carfilzomib in patients with relapsed/refractory lymphoma shows complete responses in relapsed and refractory T-cell lymphomas
.
Blood
.
2016
;
128
(
22
):
2991
.
23.
Falchi
L
,
Lue
J
,
Amengual
JE
, et al
.
A phase 1/2 study of oral 5-azacitidine and romidepsin in patients with lymphoid malignancies reveals promising activity in heavily pretreated peripheral T-cell lymphoma (PTCL)
.
Blood
.
2017
;
130
(
suppl 1
):
1515
.
24.
Amengual
JE
,
Lichtenstein
R
,
Lue
J
, et al
.
A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma
.
Blood
.
2018
;
131
(
4
):
397
-
407
.
25.
Federico
M
,
Bellei
M
,
Luminari
S
, et al
.
CD30+ expression in peripheral T-cell lymphomas (PTCLs): a subset analysis from the international, prospective T-cell project
.
J Clin Oncol
.
2015
;
33
(
15
):
8552
.
26.
Horwitz
SM
,
Advani
RH
,
Bartlett
NL
, et al
.
Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin
.
Blood
.
2014
;
123
(
20
):
3095
-
3100
.
27.
Ali
K
,
Soond
DR
,
Pineiro
R
, et al
.
Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer [published correction appears in Nature. 2016;535(7613):580]
.
Nature
.
2014
;
510
(
7505
):
407
-
411
.
28.
Horwitz
SM
,
Moskowitz
AJ
,
Jacobsen
ED
, et al
.
The combination of duvelisib, a PI3K-delta,gamma inhibitor, and romidepsin is highly active in relapsed/refractory peripheral T-cell lymphoma with low rates of transaminitis: results of parallel multicenter, phase 1 combination studies with expansion cohorts
.
Blood
.
2018
;
132
(
suppl 1
):
683
.
29.
Horwitz
SM
,
Koch
R
,
Porcu
P
, et al
.
Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma
.
Blood
.
2018
;
131
(
8
):
888
-
898
.
30.
Dreyling
M
,
Morschhauser
F
,
Bouabdallah
K
, et al
.
Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma
.
Ann Oncol
.
2017
;
28
(
9
):
2169
-
2178
.
31.
Lemonnier
F
,
Dupuis
J
,
Sujobert
P
, et al
.
Treatment with 5-azacytidine induces a sustained response in patients with angioimmunoblastic T-cell lymphoma
.
Blood
.
2018
;
132
(
21
):
2305
-
2309
.
32.
Mossé
YP
,
Voss
SD
,
Lim
MS
, et al
.
Targeting ALK with crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: a Children’s Oncology Group Study
.
J Clin Oncol
.
2017
;
35
(
28
):
3215
-
3221
.
33.
Chiarle
R
,
Voena
C
,
Ambrogio
C
,
Piva
R
,
Inghirami
G
.
The anaplastic lymphoma kinase in the pathogenesis of cancer
.
Nat Rev Cancer
.
2008
;
8
(
1
):
11
-
23
.
34.
Bandini
C
,
Pupuleku
A
,
Spaccarotella
E
, et al
.
IRF4 mediates the oncogenic effects of STAT3 in anaplastic large cell lymphomas
.
Cancers (Basel)
.
2018
;
10
(
1
):
E21
.
35.
Jacobsen
ED
,
Weinstock
DM
.
Challenges and implications of genomics for T-cell lymphomas
.
Hematology (Am Soc Hematol Educ Program)
.
2018
;
2018
:
63
-
68
.
36.
Moskowitz
AJ
,
Jacobsen
E
,
Ruan
J
, et al
.
Durable responses observed with JAK inhibition in T-cell lymphomas
.
Blood
.
2018
;
132
(
suppl 1
): 2922.
37.
Feldman
AL
,
Sun
DX
,
Law
ME
, et al
.
Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas
.
Leukemia
.
2008
;
22
(
6
):
1139
-
1143
.
38.
Pechloff
K
,
Holch
J
,
Ferch
U
, et al
.
The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma
.
J Exp Med
.
2010
;
207
(
5
):
1031
-
1044
.
39.
Horwitz
SM
,
Feldman
TA
,
Hess
BT
, et al
.
The novel SYK/JAK inhibitor cerdulatinib demonstrates good tolerability and clinical response in a phase 2a study in relapsed/refractory peripheral T-cell lymphoma and cutaneous T-cell lymphoma
.
Blood
.
2018
;
132
(
suppl 1
):
1001
.
40.
Heavican
TB
,
Bouska
A
,
Yu
J
, et al
.
Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma
.
Blood
.
2019
;
133
(
15
):
1664
-
1676
.
41.
Ng
SY
,
Brown
L
,
Stevenson
K
, et al
.
RhoA G17V is sufficient to induce autoimmunity and promotes T-cell lymphomagenesis in mice
.
Blood
.
2018
;
132
(
9
):
935
-
947
.
42.
Ng
SY
,
Yoshida
N
,
Christie
AL
, et al
.
Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models
.
Nat Commun
.
2018
;
9
(
1
):
2024
.
43.
Koch
R
,
Christie
AL
,
Crombie
JL
, et al
.
Biomarker-driven strategy for MCL1 inhibition in T-cell lymphomas
.
Blood
.
2019
;
133
(
6
):
566
-
575
.
44.
Pro
B
,
Advani
R
,
Brice
P
, et al
.
Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study
.
J Clin Oncol
.
2012
;
30
(
18
):
2190
-
2196
.
45.
Delarue
R
,
Dupuis
J
,
Sujobert
P
, et al
.
Treatment with hypomethylating agent 5-azacytidine induces sustained response in angioimmunoblastic T cell lymphomas
.
Blood
.
2016
;
128
(
22
):4164.
You do not currently have access to this content.