NcXHF

NOVEL TREATMENTS FOR T-CELL LYMPHOMA
sequently attributed to antiemetic therapy and clinically signifıcant
dysrhythmias were not seen. Romidepsin gained
FDA approval in 2011 for patients with PTCL who have at
least one prior systemic therapy. Chihara et al reported a
single-center phase I study to determine the safety profıle of
romidepsin administered on days 1 and 4 with ifosfamide/
carboplatin/etoposide (ICE), with the hope that this combination
would improve the CR rate over ICE alone and thus
facilitate a greater proportion of patients receiving SCT. 30
The main toxicities were hematologic, with reversible grade 3
or greater thrombocytopenia in 87% of patients, and 5/7
(71%) response-evaluable patients achieved CR. This encouraging
preliminary observation requires further confırmation
in an expanded cohort and enrollment is ongoing.
Belinostat. Belinostat is a pan-HDAC inhibitor derived from
hydroxamic acid that was evaluated in a single-arm phase II
study with a dosing schedule of 1,000 mg/m 2 for days 1
through 5 in a 3-week cycle until progression or unacceptable
toxicity. 31 Among 120 patients with PTCL confırmed by central
pathology review, the ORR was 26% (CR 10%). As with
romidepsin, responses were rapid (median time to response
5.6 weeks) and the median DOR was 8.3 months at the time
of initial reporting. The major toxicities were hematologic
(grade 3 anemia, neutropenia, and thrombocytopenia in
10, 13, and 13%, respectively). 31 Of note, belinostat appears
to induce grade 3 or greater thrombocytopenia less frequently
than romidepsin. On the basis of this study, in 2014
belinostat received accelerated FDA approval for patients
with relapsed/refractory PTCL.
Brentuximab Vedotin
Although “naked” monoclonal antibodies (mAbs) against
CD30 showed preclinical promise, clinical activity in patients
with CD30 lymphomas was disappointing. 32 Brentuximab
vedotin (BV) was designed to improve effıcacy by conjugating
the anti-CD30 mAb to the antimicrotubule agent
monomethylauristatin E (MMAE). Binding to CD30 on the
cell surface results in proteolytic release, internalization, and
lysosomal uptake of MMAE, and tubule disruption, cell cycle
arrest, and apoptosis. 33 ALCL has uniform strong CD30 expression,
and on the basis of positive data from BV phase I
trials, 34,35 a multicenter phase II study in patients with relapsed/refractory
systemic ALCL (ALK-positive and
-negative) was conducted. 36 Fifty-eight patients with a median
number of two prior treatments were treated with 1.8
mg/kg BV intravenously every 3 weeks for up to 16 doses.
The ORR was 86% (CR 57%) with 97% of patients having a
reduction in tumor volume; responses occurred after a median
of 6 weeks and the median DOR was 12.3 months. The
most common toxicities were nausea, fatigue, GI disturbance,
rash, and neutropenia (mostly grade 1 to 2). Peripheral
sensory neuropathy was mainly grade 1 (all grades, 41%;
grade 3, 12%) and was manageable with dose reductions and
delays. Rare but potentially fatal adverse events reported include
posterior multifocal leukoencephalopathy and pancreatitis.
37 Horwitz et al treated 35 patients with non-ALCL
PTCL subtypes (which have variable CD30 expression) using
a similar study design. 38 The patients included in this study
had either AITL (13 patients) or PTCL-NOS (22 patients);
among these two histologic subtypes the ORR was 54% and
33% and the CR was 38% and 14%, respectively. Interestingly,
CD30 expression by immunohistochemistry did not
correlate with clinical outcomes, thus it could be hypothesized
that MMAE diffuses out of the apoptotic tumor cell and
exerts local effects on the tumor microenvironment. BV was
approved by the FDA in 2011 for patients with systemic
ALCL having failed at least one prior systemic therapy, and at
the time of writing has National Comprehensive Cancer Network
compendium class 2A listing for the treatment of patients
with relapsed non-ALCL CD30 PTCL.
Alemtuzumab
CD52 is a pan-lymphoid antigen with variable expression in
PTCL. 39 The anti-CD52 mAb alemtuzumab was used as a
single agent in two small European studies in patients with
pretreated PTCL. 40,41 Enblad et al treated 14 patients with 30
mg alemtuzumab administered intravenously three times
weekly for up to 12 weeks. 40 Despite chemoprophylaxis with
trimethoprim/sulfamethoxazole and valaciclovir, fatal opportunistic
infections occurred in 5/14 (35%) patients, resulting
in early study termination. The observed ORR was
36%. Interestingly, Zinzani et al showed that a reduced dose
(10 mg) and a shorter schedule was better tolerated and effective,
with an ORR of 50% in six patients with PTCL. 41
However, the toxic deaths that occurred in the fırst study
have dampened enthusiasm for further development in patients
with pretreated PTCL.
Mogamulizumab
Mogamulizumab, a defucoslyated mAb against chemokine
receptor-4 (CCR4), was found to have single-agent activity in
patients with relapsed/refractory T-cell lymphomas in a
phase I study. 42 Ogura et al performed a phase II study in
Japanese patients with relapsed/refractory T-cell lymphoma
with 1.0 mg/kg mogamulizumab administered intravenously
weekly for 8 weeks. 43 Among 37 patients treated, the median
number of prior therapies was two and the main histologic
subtypes were PTCL-NOS (16 patients), AITL (12 patients),
and CTCL (8 patients). The ORR was 35% (CR 13%), with a
median PFS of 3.0 months. The main toxicities reported were
neutropenia (any grade, 38%; grade 3, 19%), fever (grade
1–2, 30%), infusion reaction (grade 1–2, 24%), and skin disorders
(any grade, 51%; grade 3, 11%). Although CCR4 expression
by immunohistochemistry was required for study
entry, there was little correlation between expression of target
antigen and response, similar to the data for BV and
CD30. The authors hypothesized depletion of CCR4 regulatory
T (T reg ) cells, resulting in an increase in the number of
CD8 cytotoxic T-cells, as a mechanism of tumor control,
and on the basis of these data mogamulizumab gained approval
for the treatment of relapsed PTCL in Japan in 2014.
Zinzani et al performed a multicenter European phase II
study with 38 patients and reported a lower ORR of 11% with
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