Oleg E. Akilov, MD, PhD and Larisa Geskin, MD


Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA

ABSTRACT

A variety of novel therapeutic modalities have recently become available for patients with cutaneous T cell lymphoma (CTCL). In particular, with recent FDA approvals of the three new agents vorinostat (Zolinza®), romidepsin (Istodax®), and pralatrexate (Folotyn®) CTCL treatment has been transformed. Here, we offer a brief overview of these agents and discuss their place in the spectrum of current therapies for CTCL.

Key Words:
CTCL, cutaneous T-cell lymphoma, therapy

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous
group of malignancies of mature memory T lymphocytes.
Mycosis fungoides (MF) is the most common variant of CTCL,
representing about 50% of all cases. Sézary syndrome is a
leukemic variant, affecting about 5% of patients with CTCL.1
Diagnosis is established by skin biopsy, followed by staging workup,
which may include radiologic imaging studies and evaluation
of the lymph nodes, blood, bone marrow, and internal organs for
systemic involvement, as indicated by initial patient presentation.

While numerous therapeutic options are available and recent
reports show improved survival of CTCL patients over historic
controls, suggesting the potential benefit of current regimens, no
therapy has been shown to be curative. Thus, the goal of therapy
is to induce long-term remission without further compromising
a patient’s immune system or quality of life. In general, MF
treatment is divided into two broad categories: skin-directed and
systemic therapies. Skin-directed therapy is the key component
in management of early disease, while systemic therapy is
essential in more advanced cases. Systemic therapy can be further
separated into various categories, either based on the mechanism
of action of the systemic agent (e.g., biological modifiers such
as interferons, retinoids, and rexinoid; histone deacetylase
inhibitors; and traditional chemotherapeutic agents, such as
doxorubicin and gemcitabine) or by the number of agents used
to treat a patient (e.g., monotherapy vs. multiagent combination
therapy).

Considering the overall protracted course of CTCL, its indolent
character, immunocompromised status of the patient, and
absence of definitive therapy, the treatment choices for a particular
patient should be made after carefully weighing the risk-benefit
ratio. Therapies offering fewer known adverse effects with greater potential benefits should be attempted first, while aggressive
multiagent chemotherapy contributing to immunosuppression
should be reserved for end-stage palliation.

Within recent years, there has been an explosion of basic and
clinical research in CTCL leading to an escalating number of
clinical trials in the field of cutaneous lymphoma. For example,
according to a search of ClinicalTrials.gov, from 1996-2000 there
were only 66 clinical trials in CTCL, while the number of studies
nearly doubled to 121 from 2001-2005, and from 2006-2010 the
volume tripled to 219. Within only the last 4 years, the US FDA
approved three novel agents (i.e., vorinostat, romidepsin, and
pralatrexate) for use in CTCL and/or its variants, whereas within
the previous 15 years only two agents (bexarotene and denileukin
diftitox) received an official indication for CTCL.

Many other interesting agents currently in clinical trials have
already demonstrated efficacy and safety in CTCL. The list
includes, but is not limited to, novel histone deacetylase inhibitors
(HDIs), novel antibodies (e.g., anti-CD4 and anti-CD30), purine
nucleoside phosphorylase (PNP)-inhibitor (forodesine), and
immunomodulators (e.g., CpGs). In addition, there are several
combination therapies (e.g., pralatrexate and bexarotene,
romidepsin and electron beam radiation) under clinical
investigation to explore their potential benefits as integrated
treatment and to establish the optimal dosing regimen. Our
review will focus on new developments in this field.

Skin-Directed Therapies

Various topical agents are not only considered to be mainstays of
therapy in cases of CTCL with involvement limited to the skin, but
they can also be useful as a palliation treatment in patients with
advanced disease (Table 1). Widely used topical therapies include corticosteroids, nitrogen mustard, carmustine, topical retinoids,
and rexinoid (bexarotene), as well as ultraviolet light therapy and
body irradiation. These agents/methods may be used alone or in
combination with each other.

A number of other skin-directed therapies are available, including
topical tacrolimus, imiquimod, and photodynamic therapy
(PDT). These treatments are not FDA-approved for use in CTCL,
but their effectiveness is well documented in the literature. We
will examine only selected newer topical therapies in this review.

Topical Tacrolimus

Topical tacrolimus (Protopic®) has been approved for use
in atopic dermatitis. It is as effective as mid- to low-potency
glucocorticoids and is used on facial skin and intertriginous
areas in patients with MF. A major advantage of tacrolimus
when compared with steroids is that it does not suppress
collagen synthesis, and therefore, does not cause skin atrophy.2,3
However, because therapy with calcineurin inhibitors in CTCL is
controversial, tacrolimus should be limited to short-term use on
small areas of skin.

Drug/Mode of Therapy
Corticosteroids (various potencies)
Nitrogen mustard
Carmustine
Topical retinoids
Topical rexinoid (bexarotene)
Ultraviolet light therapy

—  Psoralen + UVA (PUVA), narrowband UVB, and UVB

Electron beam radiation (localized and total skin)
Topical tacrolimus
Imiquimod
Photodynamic therapy (PDT)
Table 1. Skin-directed therapies for CTCL

Imiquimod

Imiquimod (Aldara®) is a relatively new topical immunomodulator
that is extremely effective in the treatment of
condylomata acuminata (genital warts), actinic keratoses,
basal cell carcinomas, keratoacanthomas, and other cutaneous
malignancies. Several groups have reported the effectiveness of
imiquimod in early patch MF.8,9 It should be used three times per
week for 3 months. The time to response in some patients can be
as short as 2 weeks. Long-term follow-up data is not available at
this time.

Photodynamic Therapy

Photodynamic therapy (PDT) is a photochemistry-based
modality utilizing the properties of photosensitizers (PS) to
induce singlet oxygen and reactive oxygen species upon light
irradiation. Out of the broad chemical spectrum of PS, only a
PS precursor, 5-aminolevulinic acid (ALA) and its derivative
(methyl aminolevulinate hydrochloride), have FDA approval
for use in dermatology and have been tested for CTCL. Several
investigations have appraised ALA-PDT as a prospective modality for CTCL. Orenstein et al. observed that malignant
cells in CTCL plaques have a greater ability to convert ALA into
protoporphyrin IX than peripheral blood lymphocytes.4 High
expression of CD71 (transferring receptor) on the surface of the
malignant lymphocyte may be a reason for higher production
of protoporphyrin IX due to higher turnover of iron.5 The
benefit of PDT for CTCL is considerably modest, and hence, it is
generally reserved as forth-line therapy. While PDT is efficient for
patch/plaque stage of MF, ALA-PDT is not useful for the tumor
stage of CTCL, due to insufficient penetration of PS and light
during topical application.6 It may be useful for resistant cases of
localized plaques, particularly on the head.7

Systemic Therapies

Several novel systemic agents have been recently added to the
assortment of therapies available for CTCL. Previous FDAapproved
therapies include oral bexarotene and denileukin
diftitox. Here, we will focus on agents that have been recently
approved for CTCL or demonstrated some promising preliminary
results in clinical trials.

Histone Deacetylase Inhibitors (HDIs)

Epigenetic modulation is an important mechanism of regulation
in gene expression. Histone deacetylase inhibition increases
acetylation of lysine residues that form the octomeric histone
core of chromatin, thereby decreasing the ability of the histones to
bind to DNA. This decreased binding allows chromatin expansion,
permitting transcription of the tumor suppressor genes. However,
HDIs affect acetylation globally and may have wider effects
on various cellular functions. Two novel HDIs (vorinostat and
romidepsin) were recently approved by the US FDA for use in
patients with CTCL.10,11

Vorinostat

Vorinostat (suberoylanilide hydroxamic acid, Zolinza®) is the
first HDI approved by the US FDA in October 2006 for cutaneous
manifestations of CTCL in patients with progressive, persistent,
or recurrent disease on or following two systemic therapies.1 The
clinical response endpoint in a pivotal phase II clinical trial was
exclusively improvement in skin manifestations of the disease,
as measured by a Modified Severity Weighted Assessment Tool
(mSWAT) score. In this clinical trial, formal assessment of the
disease in the lymph nodes, blood, and visceral organs was
not done for calculation of the clinical response rate. This trial
demonstrated an overall response rate (ORR) of 32%; for patients
with advanced CTCL it was slightly less (30%).12 Of the responding
patients, 98.6% exhibited a partial response (PR). Median time to
response (TTR) was 56 days; time to progression (TTP) was 168
days. Overall, 32% of patients experienced pruritus relief. The
most common drug-related adverse events were diarrhea, fatigue,
nausea, and anorexia. Bexarotene failure was one of the inclusion
criteria for this clinical trial. Many patients were refractory to
other therapies (on average, patients failed 3.5 prior therapies).
Therefore, vorinostat appears to work in a manner that is different
and non-cross resistant to other CTCL treatments. Vorinostat is
not an immunosuppressive agent, though some degree of bone
marrow suppression may occur. Vorinostat has been shown to
be safe and effective, with acceptable tolerability, when used
long-term.10,13

In clinical practice, the standard approach is to use a combination
of therapeutic agents to achieve an optimal outcome. However,
no clinical studies have been conducted to test the most effective
combinations. A recent practical review of CTCL patients treated
with vorinostat in combination with various other therapeutic
modalities, including narrowband UVB, bexarotene, and
interferon, demonstrated better clinical outcomes in 6 of 14
patients. Importantly, 11 of 14 patients experienced significant
improvement in their pruritus score, which is one of the major
issues affecting quality of life.14 We have also previously described
a patient with refractory Sézary syndrome who responded well to
the combination of vorinostat with extracorporeal photopheresis;
the clinical response may be theoretically explained through the
further induction of cell cycle arrest and apoptosis of malignant
T lymphocytes.15

Romidepsin

Romidepsin (depsipeptide, FK-228, Istodax®) is a cyclic peptide
that selectively inhibits histone deacetylase isotypes 1, 2, 4 and 6.
Romidepsin, like other HDIs, was shown to induce cell cycle
arrest in both G1 and G2/M phases of DNA replication and to
trigger apoptosis in several cell lines.16 Generally, romidepsin
is well tolerated; common side-effects include fatigue, nausea,
vomiting, and transient thrombocytopenia and neutropenia.17
A recent phase II multicenter clinical trial examining response
rates in patients with MF (stage IB-IV) resulted in US FDA
approval of this drug for clinical practice.11 Romidepsin was
evaluated in two international multicenter open-label phase II
clinical studies involving a total of 167 patients. In pooled
analysis, the ORR was 35% based on evaluation of response in all
parameters (i.e., skin, nodes, blood, and visceral involvement);
with median response duration of 14 months in one study and
11 months in the other study. Complete responses (CR) were
observed in 6% of those studied.11 Side-effects included nausea,
fatigue, anorexia, electrocardiograph T-wave changes, anemia,
dysgeusia, neutropenia, and leucopenia. However, romidepsin
monotherapy may not be sufficient for maximal benefit, and
hence, the continued search for adjuvant measures capable of
providing synergistic effects is needed. We have observed durable
and prolonged clinical responses at the radiotherapy site in
patients receiving local electron beam therapy while enrolled in
the romidepsin clinical trial. Such synergy may find a clinical
application, although further clinical trials should be performed
to formally test the efficacy and safety of this combination.

Monoclonal Antibodies

Alemtuzumab (Campath-1H, Campath®) is a humanized IgG1
monoclonal antibody that targets the CD52 antigen. An ORR of
50% in a small cohort of patients has been reported.18,19 Low-dose
alemtuzumab is safe and effective in very elderly Sézary syndrome
patients.20 Alemtuzumab effectively depletes leukemic cells from
the blood of these patients. Subcutaneous (SC) administration
of low doses on an as needed basis has been effective in Sézary
syndrome patients.21 A recent update of this therapeutic
schema for patients with Sézary syndrome was proposed by
Quaglino et al.22 The authors have suggested starting with
3 mg of SC alemtuzumab on day 1, then administering 10 mg on
alternating days until the circulating Sézary cell count drops below
1000/mm3. Once the Sézary cell count rises above 2000/mm3,
another SC alemtuzumab dose of 10 mg can be administrated.

Such an approach can help to avoid complete obliteration of the
lymphocytes and reduce the rate of opportunistic infections.

Extracorporeal Photopheresis

Extracorporeal photopheresis (ECP) is an approved palliative
treatment for CTCL. The novel continuous flow separation (CFS)
system (THERAKOS™ CELLEX™) has been developed based
on the current UVAR®XTS™ device and is designed to reduce
treatment times and extracorporeal volumes. A safety and efficacy
study assessed patients receiving ECP with the novel UVAR®
CFS system for up to 6 months in their previously established
regimen. Thirteen patients were enrolled and 12 completed the
study; 155 ECP treatments were initiated and 153 were completed.
This new ECP system improved treatment times and decreased
extracorporeal volumes while demonstrating an acceptable safety
profile in the treatment of Sézary syndrome patients.23

Chemotherapy

Neither single agent nor multiagent therapy is curative in MF.
Additionally, single or multiagent chemotherapy results in a
higher incidence of transformation to large cell lymphoma,
which carries a worse prognosis than the original diagnosis.24
Because ORR and disease free survival are generally higher after
combination therapy, single agent chemotherapy is rarely used.
However, use of multiagent chemotherapy results in increased
immunosuppression and higher risk of serious infections,
leading to death in a majority of patients who develop these
complications.25 A number of single agent chemotherapeutic
agents have been reported to be effective in CTCL. For example,
gemcitabine (Gemzar®) demonstrated high clinical efficacy in
advanced and refractory CTCL, with a 70.5% response rate,26
while pegylated doxorubicin used in advanced MF has resulted in
an even higher overall response of 88%.27

Pralatrexate

Pralatrexate (Folotyn®) is a new antifolate analogue that is
FDA-approved for relapsed or refractory peripheral T-cell
lymphoma. The relative specificity of antifolates for malignant
cells is a result of over-expression of their receptor, reduced folate
carrier-1 (RFC-1). Pralatrexate was specifically designed to have
significantly higher affinity to RFC-1 as compared with other
antifolates. In addition, polyglutamylation of pralatrexate secures
retention of this drug within the cancer cell. The interference with
dihydrofolate reductase affects synthesis of deoxythymidine and
the purine DNA nucleotides, which ultimately results in arrest of
the cell cycle.28,29

Pralatrexate was evaluated in a pivotal phase II non-randomized,
open-label international study. The trial enrolled 115 patients,
111 of whom received intravenous pralatrexate 30 mg/m2 weekly
for 6 weeks every 7 weeks, supplemented with B12 and folic acid;
109 patients were evaluable for efficacy. The ORR was 27% with
a CR of 10%, and a PR of 17%. The majority of responses were
observed after the first cycle. Adverse events included mucosal
inflammation and thrombocytopenia.30

Lenalidomide

Lenalidomide (Revlimid®), a thalidomide analogue, is
an immunomodulatory agent with antiangiogenic and
antineoplastic properties. Querfeld et al. reported an ORR of
28% in CTCL patients who received a median of nine cycles of
therapy consisting of 25 mg lenalidomide daily for 21 days of a 28-day cycle. Median TTR was 6 months. However, high toxicity
symptoms (i.e., anemia, fatigue/malaise, skin burning, pruritus,
diarrhea, and lower leg edema) resulted in discontinuation of the
drug in 40% of patients.31,32

Bortezomib

Bortezomib (Velcade®) is a reversible 26S proteasome inhibitor
approved by the US FDA for the treatment of multiple myeloma
and mantle cell lymphoma. A phase II trial demonstrated
considerable clinical efficacy of bortezomib (the ORR was 67%)
as single agent therapy in patients with relapsed or refractory
CTCL.33

Stem Cell Transplant

The lifetime expectation for transformed MF and Sézary
syndrome is less than 2.5 years.34 Stem cell transplantion (SCT) is
a promising approach aimed at providing a cure or increasing life
expectancy. Autologous SCT showed very limited efficacy in most
patients with CTCL, since 60% of these patients experienced an
early relapse (median time to relapse was 120 days).35 In another
study, relapse occurred in 50% of patients in less than 100 days.36
The CR of 58% in the first US study by Duvic et al.37 is similar to
the 60.5% reported by Duarte et al.38 The relapse rate was shown
to be lower after allogeneic SCT (39% of patients), however, time
to relapse was shorter (50 days).37 Nevertheless, SCT carries a
risk of significant toxicity and fatal complications, particularly in
older patients. Careful patient selection and proper timing of SCT
are critical factors in successful therapy.

Conclusion

Because CTCL is an indolent malignancy of T cells with excellent
prognosis in early stages, the treatment approach should be
conservative with skin-directed therapies (nitrogen mustard,
topical glucocorticoids, topical bexarotene, and imiquimod)
combined with light therapy, low-dose interferon, low-dose
methotrexate, other biologics, or single agent chemotherapy. The
survival of patients treated with aggressive chemotherapy is not
different from the survival of patients treated conservatively, but
aggressive chemotherapy results in greater toxicity. Because no
curative therapy exists, the goal of treatment is to prevent disease
progression to more advanced stages and to preserve the patient’s
quality of life for as long as possible.

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