Drs. Girardi and Edelson provide a concise discussion of current
issues surrounding the management of patients with cutaneous T-cell
lymphomas. They discuss a number of current theories regarding
etiology and pathogenesis and provide a brief overview of the many
therapies that are currently available to treat mycosis
fungoides/Sézary syndromethe most common form of
patch/plaque cutaneous T-cell lymphoma (CTCL).
The importance of the authors discussion regarding variant
forms and presentations cannot be emphasized strongly enough. Mycosis
fungoides/Sézary syndrome can manifest in a variety of ways,
from isolated patches or plaques to involvement of the skin, lymph
nodes, and peripheral blood. Regardless of the extent or stage of
this disease, however, many of the same treatment approaches are appropriate.
In contrast, treatment of the nonmycosis fungoides/Sézary
syndrome forms of CTCLsuch as peripheral non-Hodgkins T-cell
lymphomas with skin involvement, human T-cell lymphotropic virus
type 1 (HTLV-I)related acute T-cell lymphoma/leukemia, or the
CD30-positive family of lymphoproliferative disordersoften
requires other modalities not commonly applied in the treatment of
classic mycosis fungoides.
For this reason, we find it extremely helpful to evaluate these
patients in the setting of a multidisciplinary clinic, with
participation in diagnosis and management by dermatologists,
dermatopathologists, hematopathologists, hematologists, and radiation
oncologists. This allows for a complete review of pathologic material
(including routine hematoxylin and eosin [H&E]-stained slides),
immunohistochemistry or flow cytometry data, and gene rearrangement
studies. With this approach, we can provide a consensus regarding
therapy that is tailored to specific subtypes of CTCL.
Etiology of Mycosis Fungoides/Sézary Syndrome
The authors advance the theory that an as yet unidentified retrovirus
infects the Langerhans cells of the skin. In turn, these professional
antigen-presenting cells are stimulated to produce cytokines that
activate T-helper cells, thereby resulting in the ultimate formation
of the neoplastic cells of mycosis fungoides/Sézary syndrome.
This theory represents speculation on the authors part and
requires significant basic scientific confirmation before it can be accepted.
Other theories have been advanced, including those with a role for
infection/colonization of skin by staphylococcal organisms (some of
which are able to stimulate T-helper lymphocytes) or exposure of skin
to other agents that cause the release of cytokines from
keratinocytes (which stimulate the proliferation of T-helper cells).
Based on the cytokine profile expressed by the neoplastic T
lymphocytes, studies of the T-helper cell subsets (TH1 and TH2)
responsible for this disease are leading to new therapeutic
strategies. No specific chromosomal abnormalities have been
consistently noted that would associate a particular oncogene or
suppressor gene with this disease.
Finally, there are proponents of the theory that this disease does
not result from stimulation of T lymphocytes at all, but rather,
represents a lymphoaccumulative disorder caused by dysregulated
apoptosis signaling in the neoplastic clone. This hypothesis has also
stimulated the development of novel therapeutic interventions.
Shortcomings of Published Trials
Drs. Girardi and Edelsons discussion of therapy for mycosis
fungoides/Sézary syndrome highlights alternative strategies
and reflects the opinions of the authors. Unfortunately, much of the
literature regarding the treatment of this disorder lacks the rigor
of oncologic studies in other disease sites. Many published
trials of agents used in this disease represent anecdotal
outcomes of a handful of patients (often 5 to 10) treated in a
sometimes nonuniform, uncontrolled fashion.
Until recently, very few adequate phase I or phase II trials have
been performed for systemic agents in mycosis fungoides/Sézary
syndrome. Likewise, few randomized therapeutic trials have been
performed, thereby limiting comparisons of active approaches. Thus,
treatment decisions often reflect the biases of individual centers
and do not represent a true consensus of all clinical investigators.
Managing Mycosis Fungoides/Sézary Syndrome
At Northwestern University, we agree with Drs. Girardi and Edelson
that immunomodulatory approaches can affect the outcomes of patients
with mycosis fungoides/Sézary syndrome. The presence of
cytotoxic, infiltrating T lymphocytes in early-stage plaque lesions,
along with their gradual loss with disease progression, suggest that
indiscriminate suppression of the immune system may be counterproductive.
In addition, the authors suggestion that photopheresis results
in a specific cytotoxic response by the host immune system through
vaccination or reinfusion is intriguing and, in fact, led
us to the theory that psoralen plus ultraviolet A light (PUVA)
therapy works via similar mechanisms. It has been suggested that the
exposure of the T lymphocytes to photoactivated psoralen compounds in
the presence of ultraviolet light induces apoptosis via cross-linking
of DNA and inhibition of protein production. Given the systemic
nature of this disease (even in early-stage patients) and the
trafficking of cells within the lymph nodes and blood, neither
approach would be expected to result in complete and durable
remissionsunless secondary effects were beneficial. The
exposure of components of apoptotic malignant clones to
antigen-presenting cells may allow the host immune system to respond
to novel antigens associated with the neoplastic population with a
subsequent immune response.
This theory prompted us to test PUVA with systemic interferon
administration, whereby we speculated that synergistic immune
approaches would result in higher response rates and more durability.
We have demonstrated that this combination results in approximately
90% response rates in advanced-stage, pretreated patients. More
recently, a European randomized trial demonstrated that the
combination of PUVA plus interferon was associated with higher rates
of response induction (80% vs 60%) than interferon plus a retinoid
(acitretin [Soriatane]), thereby confirming our initial findings.
We have, therefore, treated most patients with advanced disease with
PUVA plus interferon, resulting in rapid response induction and often
durable benefits. However, unanswered questions persist, for example,
regarding the optimal duration of interferon therapy and whether
similar benefits can be obtained with combinations of interferon and
other topical modalities.
Once frontline treatment has failed, the progression of CTCL mimics
that of low-grade B-cell lymphomas. Many treatment approaches
demonstrate activity, but typical response rates and durability
decrease with subsequent interventions. Unlike patients with
low-grade B-cell lymphomas, CTCL patients are often symptomatic,
requiring therapy to control infection and deal with cosmetic issues.
Thus, many patients with CTCL are treated sequentially with
palliative topical therapies, such as topical chemotherapy, limited
or total skin electron-beam radiotherapy, and topical steroids or
retinoids. Ultimately, many patients require systemic therapy.
Because we believe that immunosuppression is potentially harmful to
patients with CTCL, we do not use any immunosuppressive or cytotoxic
chemotherapy until late in the disease. A spectrum of single agents
and combination regimens have demonstrated efficacy, but since only
palliation can be achieved, the risk/benefit of each approach must be
Due to their lympholytic effects, the purine analogsfludarabine
(Fludara), pentostatin (deoxycoformycin [Nipent]), and cladribine
(chlorodeoxyadenosine [Leustatin])have great theoretical
appeal. However, they must be used with caution because of their
immunosuppressive consequences and associated opportunistic infections.
Data from the National Cancer Institutes randomized clinical
trial suggests that aggressive chemotherapy/radiation therapy
combinations do not improve survival vs sequential palliative
approaches with less toxicity. These data have shifted our focus
to clinical trials of novel therapies. Recent investigations of
targeted approaches, including the diphtheria toxininterleukin-2
(IL-2) fusion protein denileukin diftitox (Ontak) and new retinoids
(eg, oral bexarotene [Targretin]), have led to the Food and Drug
Administration (FDA) approval of agents with novel mechanisms of
action. Our interest in manipulating T-lymphocyte subsets with
cytokines such as IL-2 (Proleukin) and interleukin-12 remains a priority.
Finally, we are pursuing studies of the mechanisms of drug resistance
in the neoplastic cells of patients with mycosis fungoides/Sézary
syndrome. We hope to identify subsets of patients who are most
likely to respond to cytotoxic chemotherapy. We are also using
allogeneic bone marrow transplantation with donor lymphocyte
infusions for the rare young patients with aggressive, refractory
disease who are fortunate to have a matched-related donor.
In summary, much remains to be defined regarding the management of
patients with CTCL. Accrual to clinical trials remains a priority, to
best define the use of current and potential agents.
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versus interferon-2a plus PUVA in patients with cutaneous T-cell
lymphoma stages I and II. Blood 92:3578-3581, 1998.
3. Kaye FJ, Bunn PA Jr, Steinberg SM, et al: A randomized trial
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