NcXHF

CHEAH, OKI, AND FANALE
an ongoing German cooperative group study (EudraCT
number: 2007-001052-39).
NEW AGENTS FOR RELAPSED AND REFRACTORY
DISEASE
When treated using conventional chemotherapy alone, the
outcome of patients with relapsed or refractory PTCL is particularly
poor—a population-based registry study from the
British Columbia Cancer Agency found that the median OS
of patients with PTCL was only 5.5 months. 16 When used as a
single agent in pretreated patients, bendamustine results in
an ORR of approximately 50% with a median duration of response
(DOR) of 3.5 months. 17 Gemcitabine has a similar
ORR and the responses appear more durable. 18,19 However,
there is a substantial unmet need for more options for patients
whose disease does not respond to these therapies. Fortunately,
several agents with novel mechanisms of action
have been approved for this setting in the last 5 years, with
several others undergoing evaluation in trials for potential
future approval (Table 1).
Pralatrexate
Folates are critical for DNA synthesis and folate antagonism
was one of the earliest successful chemotherapeutic pathways.
20 Pralatrexate is an inhibitor of dihydrofolate reductase
that was designed to have increased affınity for the reduced
folate carrier and therefore accumulates within cells and exhibits
increased potency compared with methotrexate. 21 A
phase I study demonstrated promising activity in T-cell lymphomas,
22 prompting an international phase II study
(PROPEL). In this trial, 111 patients with relapsed or refractory
aggressive PTCL were treated with single-agent pralatrexate
(30 mg/m 2 administered intravenously once weekly),
achieving an ORR of 29% (CR 11%) with median DOR of
10.1 months. 23 The major toxicities seen with this agent are
cytopenias (particularly thrombocytopenia, which may be
dose limiting) and mucositis (any grade, 70%; grade 3,
22%), although there are data suggesting that prophylactic
use of leucovorin may ameliorate the latter without compromising
effıcacy. 24 On the basis of this study, in 2009 pralatrexate
gained U.S. Food and Drug Administration (FDA)
approval for patients with PTCL who have received one or
more systemic therapies.
Histone Deacetylase Inhibitors
Epigenetic therapies are useful for a range of hematologic
malignancies, particularly PTCL. Recent publications have
shown that histone deacetylase (HDAC) inhibitors have
pleiotropic downstream effects including apoptosis, senescence,
immune suppression, and angiogenesis. 25 HDACs are
a group of enzymes with both histone and nonhistone targets
that together govern chromatin conformation and gene expression.
26 Several agents in this class are effective in PTCL.
Romidepsin. Romidepsin is a cyclic, class 1-selective HDAC
inhibitor that has been used as monotherapy for relapsed or
refractory PTCL in two phase II studies. 27,28 Coiffıer et al reported
the larger study, in which 130 patients (53% PTCL-
NOS) with a median of two prior treatments received 14
mg/m 2 romidepsin intravenously once weekly for 3 of 4
weeks. 28 Responses occurred at a median of 1.8 months; the
ORR of 25% (CR 15%) was comparable across major histologic
subtypes. Responses were durable, and a recent update
of this study reported a median DOR of 28 months. 29 The
most common toxicities included fatigue, thrombocytopenia,
and gastrointestinal (GI) disturbance. Early reports
suggesting prolongation of corrected QT interval were sub-
TABLE 1. Summary of Selected Novel Agents Currently Being Evaluated for Efficacy in Peripheral T-Cell
Lymphoma
Agent Mechanism Phase n Grade 3 Toxicities ORR CRR DOR
FDA-approved agents for PTCL
Pralatrexate 23 Folate antagonist II 111 Mucositis 29% 11% 10.3 mo
Romidepsin 27,28 HDAC inhibitor II 47 Nausea, fatigue, thrombocytopenia 38% 17% 8.9 mo
II 130 Thrombocytopenia, neutropenia, infection 25% 15% 28 mo*
Brentuximab vedotin 38 Antibody-drug conjugate II 35 Neutropenia, peripheral neuropathy 41% 24% 7.6 mo
Belinostat 31 HDAC inhibitor II 129 Hematologic 26% 10% 13.6 mo
Agents under investigation in PTCL
Mogamulizumab 43 Anti-CCR4 mAb II 37 Neutropenia, rash 34% 17% 8.2 mo**
Alisertib (MLN8237) 54 Aurora A kinase inhibitor II 37 Hematologic, febrile neutropenia 24% 5% NR
Duvelisib (IPI145) 69 PI3K inhibitor I 33 Transaminitis, rash, neutropenia 47% 12% NR
Crizotinib 89 ALK inhibitor II 14 Diarrhea, vomiting, visual impairment 60% 36% 8.3 mo
Nivolumab 88 Anti-PD1 mAb I 5 Pneumonitis, rash, sepsis 40% 0% NR
Abbreviations: ORR, objective response rate; CRR, complete response rate; DOR, duration of response; PI3K, phosphoinositide-3-kinase; CCR4, chemokine receptor-4; HDAC, histone deacetylase;
ALK, anaplastic lymphoma kinase; NR, not reported; PD-1, programmed cell death-1; mAb, monoclonal antibody.
Response rates refer to patients with nodal PTCL subtypes where information available.
*Duration of response reported from updated report. 29
**Median progression-free survival of patients with PTCL achieving response.
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