Mycosis fungoides is an
indolent primary cutaneous T-cell lymphoma (CTCL), characterized by
infiltration of the skin by mature T lymphocytes. The early plaque
stage usually progresses over time, with tumors developing and the
lymph nodes and visceral organs becoming involved. Transformation to
high-grade lymphoma may also occur. Sézary syndrome is a
distinct variant characterized by generalized erythroderma and
circulating cerebriform cells in the peripheral blood. Unspecified
peripheral T-cell lymphomas with isolated skin involvement are
included among the CTCLs.
A precise diagnosis of CTCL can be difficult to make. The early
stages of mycosis fungoides may be hard to differentiate
histologically and clinically from a variety of benign and
premalignant skin conditions. More advanced disease must be
differentiated from B-cell non-Hodgkins lymphoma and myeloid
malignancies involving the skin. The circulating cells in
Sézary syndrome resemble other mature T-cell leukemias, such
as adult T-cell leukemia/lymphoma and T-prolymphocytic leukemia,
which may also present with skin involvement.
Diagnosis rests on the characteristic skin histology, peripheral
blood morphology in Sézary syndrome, and immunologic markers.
Establishing clonality using polymerase chain reaction to detect
T-cell receptor rearrangement may help differentiate CTCL from benign
conditions. Skin pathology is similar in mycosis fungoides and
Sézary syndrome, and is characterized by a dermal infiltrate
of atypical lymphoid cells that extend into the epidermis, where
clusters of cells form Pautriers microabscesses. The
circulating lymphoid cells in Sézary syndrome are
hyperchromatic, with a high nuclear-to-cytoplasmic ratio and a
characteristic convoluted or cerebriform nucleus.
The nuclear folds and indentations are seen more clearly with an
electron microscope. There are small- (Lutzner) and large-cell
variants of Sézary cells. The bone marrow is often not
involved. Surface marker analysis has shown that the malignant cell
in both mycosis fungoides and Sézary syndrome is a mature T
cell (CD2-positive, CD3-positive, terminal deoxynucleotidyl
transferase-negative). The majority of these cells have a
CD4-positive phenotype, usually restricted to the memory
T-helper subset (CD45RA-positive). The T-cell antigen CD7 is often
negative and CD25 is sometimes expressed, making it difficult to
distinguish mycosis fungoides and Sézary sydrome from adult
A variety of treatment modalities have been used in mycosis
fungoides/Sézary syndrome.[2-5] Initial choice of therapy
depends on the extent of disease. Patients with early-stage mycosis
fungoides have a good prognosis and commonly receive only skin-directed
therapy (psoralen ultraviolet light, photophoresis, electron-beam
irradiation). For patients with more advanced mycosis fungoides and
for those with Sézary syndrome, the outlook is poorer;
standard therapies, including single-agent and combination
chemotherapy, have been palliative rather than curative.
Recent studies have focused on immunomodulation, with the aim of
enhancing host antitumor responses with agents such as interferon
(Intron-A, Roferon-A) and interleukin-2 (Proleukin). Conjugated
and unconjugated monoclonal antibodies have also been used.
Pentostatin (2´-deoxycoformycin [Nipent]), a potent inhibitor of
adenosine deaminase, has activity in a wide range of lymphoid malignancies.[7-15]
Adenosine deaminase deficiency is known to be selectively toxic to
lymphoid cells.  High levels of adenosine deaminase in T cells
make T-lymphoproliferative disease an obvious target for pentostatin
therapy. Other purine analogs, such as cladribine
(2-chlorodeoxyadenosine [Leustatin]), fludarabine (Fludara), and
gemcitabine (Gemzar), have also shown activity in CTCL.[17-22]
In a large study of T-cell malignancies, we examined the role of
pentostatin in the treatment of 29 patients with CTCL: 16 with
Sézary syndrome and 13 with other CTCLs, including five with
mycosis fungoides. The median age of patients was 61 years (range, 26
to 87 years) and the male-female ratio, 2.5:1. The majority of
patients (N = 20) had received prior therapy with a variety of
topical and systemic agents (Table 1). All patients manifested skin
involvement, more than half had lymphadenopathy (57%), and
one-quarter (24%) had splenomegaly (Table
1). The median white blood cell count at presentation was 20 x 109/L.
All patients also had a mature post-thymic phenotype, with cells
from the majority being CD4-positive, CD8- negative, and CD25-negative.
Pentostatin was administered by intravenous bolus injection at a dose
of 4 mg/m²/wk for 4 weeks and then every 2 weeks until optimal
response. Three of the Sézary syndrome patients who achieved a
partial response (PR) continued to receive maintenance injections
every 2 weeks. Patients received prophylaxis with co-trimoxazole and
also, in some cases, with fluconazole (Diflucan) and acyclovir (Zovirax).
The criteria for response were as follows: a complete response (CR)
consisted of normalization of blood counts, regression of
organomegaly and skin lesions, and no residual disease in the bone
marrow; a PR consisted of a 50% reduction in these parameters.
Responses (CRs and PRs) were required to be sustained for at least 3
months. The duration of response was measured from the time of onset
of objective clinical response to the time of relapse or last
follow-up. No response was defined as less than a 50% improvement or
a response duration of less than 3 months.
The results of pentostatin treatment in these patients with CTCL are
summarized in Table 2. The
overall response rate (CR plus PR) was 35%. However, a good response
was seen only in patients with Sézary syndrome. Those patients
had an overall response rate of 62% (3 CRs and 7 PRs), compared with
no responses in patients with other CTCLs (including mycosis fungoides).
Responses were durable, with a median disease-free interval of 9
months (range, 3 to 84 months). One complete responder, who presented
with widespread systemic involvement (spleen, liver, lung, lymph
nodes, and 14 x109/L Sézary cells) and who was
resistant to CHOP (cyclophosphamide, doxorubicin, Oncovin, and
prednisone) chemotherapy remained in unmaintained CR for 7 years (ie,
the patient received no maintenance therapy; Figure
1). Another patient, who achieved a CR, received pentostatin as
first-line treatment and had a disease-free interval of 3 years.
Partial responses, which included significant skin improvement,
lasted from 3 to 12 months, and three patients who achieved PRs
received pentostatin as maintenance therapy. Symptomatic benefit,
short of a PR, was observed in three patients with other CTCLs. The
five patients with mycosis fungoides showed no objective benefit.
Pentostatin was well tolerated, with no major toxicity at the doses
administered. The most common adverse effect was mild to moderate
nausea, which was generally controlled with antiemetics. Significant
hematologic, renal, and hepatic toxicity was not observed.
Our results indicate that Sézary syndrome is the only CTCL to
benefit from therapy with pentostatin, when administered either as
first-line treatment or to previously treated patients. Among 145
patients with a variety of mature
T-cell malignancies, the highest responses to pentostatin were
observed in patients with Sézary syndrome. This
underscores the importance of making a precise diagnosis in order to
facilitate selection of treatment. The responses in patients with
Sézary syndrome were durable, with unmaintained remissions of
up to 7 years.
Pentostatin achieves good control of both the blood and skin
manifestations of Sézary syndrome and merits consideration as
first-line therapy in this disease. However, in other CTCL
conditions, our experience using pentostatin as a single agent was
disappointing. Use of pentostatin in combination or sequentially with
other cytotoxic drugs or biological response modifiers may be more effective.
Other studies using pentostatin as a single agent in CTCL have
reported response rates of 35% to 50%.[14,23-25] When used in
combination with intermittent interferon, a response rate of 41% was
reported. A comparison of our results with other studies is
complicated by the variety of ways in which researchers have
subclassified this group of diseases and the fact that some studies
do not distinguish Sézary syndrome from other CTCLs. However,
it appears that some studies have also reported that the best
responses were seen in patients with Sézary syndrome, as in
Most of the studies using other purine analogs to treat CTCL have
produced less promising results. Response rates of less than 30% with
cladribine (range, 13% to 47%)[17-20] and 19% with fludarabine have
been reported. Furthermore, significant myelotoxicity has limited
the effectiveness of these treatment regimens. A newer nucleoside
analog, gemcitabine, showed promising results in a phase II study of
13 pretreated CTCL patients (5 with mycosis fungoides and 8 with
peripheral T-cell lymphoma) with a response rate of 69% (1 CR and 8
PRs). Toxicity was minimal.
Single-agent pentostatin has produced a maximal response of 62% in
patients with Sézary syndrome. Combination strategies need to
be explored if this response rate is to be improved. However, because
patients with CTCL are already immunosuppressed by the disease,
additional toxicity must be carefully avoided.
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