 |
|
Treatment of Cutaneous T-Cell Lymphoma With Combined Immunomodulatory Therapy
A 14-Year Experience at a Single Institution
Karen Rebecca Suchin, MD;
Andrew J. Cucchiara, PhD;
Scott L. Gottleib, MD;
Jonathan T. Wolfe, MD;
Barbara J. DeNardo, RN;
William H. Macey, RN;
Patricia G. Bromley, RN;
Carmela C. Vittorio, MD;
Alain H. Rook, MD
Arch Dermatol. 2002;138:1054-1060.
ABSTRACT
| |
Objective To determine the efficacy of multimodality biologic response therapy
for patients with cutaneous T-cell lymphoma (CTCL).
Design Retrospective cohort study over a 14-year period.
Setting Tertiary care university hospital.
Patients A consecutive sample of patients was studied, all 47 of whom carried
the clinical and laboratory diagnosis of CTCL: 68% of patients had stage III
or IV disease, and 89% had circulating malignant T cells.
Interventions All 47 patients received photopheresis for 6 or more cycles. Thirty-one
patients received treatment with a combination of photopheresis and 1 or more
systemic immunostimulatory agents, including interferon alfa, interferon gamma,
sargramostim, or systemic retinoids for 3 or more months.
Main Outcome Measures Differences in pretreatment prognostic factors, response rates, and
survival between patients receiving multimodality therapy and single-modality
therapy or historical controls.
Results A total of 79% of patients responded to therapy: 26% had complete remission,
and 53% had a partial remission. Median survival from initiation of therapy
was 74 months. Median survival for patients with stages III and IV and peripheral
blood involvement was 55 months compared with 31 months for historical controls.
Compared with the photopheresis monotherapy group, the patients receiving
combination immunomodulatory therapy had a worse prognosis at the time of
treatment initiation based on multiple prognostic factors. The positive response
rates and median survival times were 84% and 74 months, respectively, compared
with 75% and 66 months, respectively, for the combination immunomodulatory
and photopheresis monotherapy groups (P = .47 for
positive response rates and P = .51 for survival).
Conclusions Patients with advanced CTCL and multiple poor prognostic factors who
receive treatment with combination immunomodulatory therapy experience higher
clinical response rates and longer survival than historical controls. Although
the group who received combination therapy had worse prognostic factors at
baseline, they had better response rates and overall survival compared with
those receiving photopheresis monotherapy.
INTRODUCTION
CUTANEOUS T-CELL lymphomas (CTCLs) are skin-invasive, T-cell, non-Hodgkin
lymphomas characterized by a clonal proliferation of malignant T lymphocytes.1-2 Early-stage disease is usually confined
to the skin as patches or plaques. As the disease progresses, patients can
develop cutaneous tumors or erythroderma and associated peripheral blood,
lymph node, and visceral organ involvement.3-6
The prognosis for patients with CTCL is dependent on stage, as determined
by type and extent of skin lesions and degree of extracutaneous involvement.6-12
Cutaneous tumors, erythroderma, peripheral blood involvement, lymph node or
visceral invasion, and eosinophilia denote a poor prognosis.10
A recent review of 106 cases of CTCL with erythroderma treated with psoralen
plus UV-A irradiation (PUVA), radiation therapy, or systemic chemotherapy,
alone or in combination, reported a median survival of approximately 43 months,
or 3.6 years, from the first treatment date.6
A variety of studies have suggested that the Sézary cell is usually
derived from the T-helper type 2 subset of CD4+ lymphocytes.13 This is reflected in the observations that the lymphoid
cells from patients with CTCL exhibit depressed cell-mediated immunity, are
deficient in interleukin (IL) 2 and interferon gamma production, and show
increased production of IL-4, IL-5, and IL-10.13-14
More recently, the malignant clonal T-cell population in CTCL has been shown
to be susceptible to cell-mediated lysis by autologous cytotoxic T lymphocytes.15 Therefore, therapy for CTCL has been directed at
shifting the immune response in favor of the T-helper type 1 or cytotoxic
lymphocyte subpopulation in an effort to enhance autologous anticlonotypic
activity against the pathogenic Sézary cells.
Extracorporeal photopheresis is a leukapheresis-based immunomodulatory
therapy that combines methoxsalen with extracorporeal UV-A irradiation to
a fraction of the peripheral blood leukocytes. Photopheresis has been shown
to selectively induce apoptosis of malignant or activated lymphocytes with
simultaneous enhancement of phagocytic activity by treated macrophages.16-19 Findings
of long-term follow-up of patients with advanced CTCL have suggested that
photopheresis produces significant improvement in quality of life and may
prolong life in comparison with historical controls with a similar burden
of disease.20-22
More recently, immunostimulatory agents such as interferon alfa, interferon
gamma, sargramostim, and systemic retinoids have been added to extracorporeal
photopheresis in an effort to further enhance cytotoxic T-lymphocyte function
and antigen presentation. However, little is known regarding the efficacy
of regimens combining multiple biologic response–enhancing therapeutic
modalities.
At our institution since 1985, we have treated 47 patients with advanced
CTCL with photopheresis for a minimum of 6 months. In addition, most of these
patients received a minimum of 3 months of therapy with interferon alfa, interferon
gamma, sargramostim, and/or systemic retinoids in combination with photopheresis.
Herein, we review our experience with combination immunomodulatory therapy
compared with photopheresis monotherapy and historical controls for the treatment
of advanced CTCL.
PATIENTS AND METHODS
PHOTOPHERESIS PROCEDURE
All patients were treated with the UVAR photopheresis system (Therakos,
West Chester, Pa) as previously described.23
The entire procedure required about 4 hours. Plasma psoralen levels were not
routinely measured. However, if a patient failed to respond after 4 or 5 cycles
of photopheresis, we measured plasma psoralen levels or empirically increased
the psoralen dose.
TREATMENT PROTOCOL
Forty-seven patients received a minimum of 6 cycles of photopheresis
between January 1985 and December 1998. All patients underwent a pretreatment
assessment, which included a physical examination, skin biopsy for definitive
diagnosis, routine laboratory studies, electrocardiography, and roentgenography
of the chest. In addition, all patients had peripheral blood examined for
the presence of atypical cells (Sézary cells). This was accomplished
by light microscopic examination of 1-µm sections of the buffy coat
as previously described.20
Most patients also had fluorescence-activated cell sorter analysis performed
on peripheral blood for the cell surface markers CD3, CD4, CD7, and CD8 and/or
Southern blot analysis of the  chain gene of the T-cell receptor to
determine whether an expanded clonal population of T cells was present. Furthermore,
most patients who had palpable lymphadenopathy before treatment had lymph
node biopsies performed. On the basis of this evaluation, patients were assigned
a disease stage according to a previously defined staging system for CTCL24 (Table 1
and Table 2).
|
|
|
|
Table 1. Staging System of Cutaneous T-Cell Lymphoma: Description of
TNMB Classification*
|
|
|
|
|
|
|
Table 2. Disease Stage According to TNM Classification*
|
|
|
Present criteria for receiving photopheresis include extensive skin
involvement and more than 5% circulating Sézary cells detected on buffy
coat analysis. However, when photopheresis was in its early development, patients
with any stage of cutaneous disease, with or without peripheral blood involvement,
were eligible for treatment. Responses in some of these early patients are
included in the present study and served to establish the current treatment
criteria.
All patients were admitted to the Hospital of the University of Pennsylvania,
Philadelphia, for therapy. Typically, patients were treated with 1 cycle of
photopheresis at 4-week intervals. Each cycle consisted of a photopheresis
treatment on each of 2 consecutive days. Patients were assessed at the time
of their hospital admissions by physical examination and routine laboratory
studies. Every 3 to 4 months, peripheral blood was collected for fluorescence-activated
cell sorter analysis and Sézary counts. In addition, if a clinical
remission was suspected and a peripheral blood T-cell clonal population had
been detected by Southern blot analysis before initiation of treatment, blood
was sent for Southern blot analysis in an effort to verify by molecular analysis
the disappearance of the malignant clone from the blood.
Initially, an attempt was made to maintain photopheresis as monotherapy
for at least 6 months before the use of adjuvant therapy. If sometime after
6 months of monotherapy a patient's clinical response slowed, was unchanged,
or worsened, adjuvant treatment was usually added. As more experience with
the common adjuvant agents was obtained and/or when a patient's pretreatment
assessment revealed particularly advanced disease defined by a markedly elevated
white blood cell count (WBC), bulky lymphadenopathy, high numbers of circulating
Sézary cells (>20%), or a markedly increased CD4+/CD8+ ratio, patients were usually started on a combination of photopheresis
with 1 or more forms of adjuvant therapy.
The most common adjuvant agents used were low doses of interferon alfa
(1.5-7.5 x 106 U, 3 to 5 times weekly), systemic retinoids
(10-50 mg of etretinate daily; 10-25 mg of acitretin daily; 10-30 mg of isotretinoin
daily; or 10-20 mg of all-trans retinoic acid daily),
sargramostim (75-125 µg subcutaneously 1 hour after photopheresis),
and interferon gamma (1-3 x 106 U 3 to 5 times weekly). Immunomodulatory
medications and doses were tailored for each patient to minimize adverse effects.
Patients were considered members of the combination immunomodulatory therapeutic
group if they received both extracorporeal photopheresis and 1 or more of
the above-listed agents simultaneously for at least 3 months.
Some of the patients received brief courses of local  irradiation
to cutaneous tumors or lymph nodes and/or focal treatment to affected skin
with topical chemotherapeutic agents (0.01% nitrogen mustard in petrolatum
or 20-40 mg of carmustine in 100 g of petrolatum) or topical steroids and/or
concurrent treatment with PUVA or UV-B irradiation. Since these forms of therapy
do not produce systemic immune-enhancing effects, they were not considered
forms of adjuvant therapy.
A complete response to therapy was defined as the regression of all
evidence of disease for at least 3 months, including skin disease, disappearance
of Sézary cells from the peripheral blood if present before therapy,
and a change in Southern blot analysis indications from clonal rearrangement
to a germline pattern. A partial response was designated as at least a 50%
reduction in skin surface area involvement and in numbers of circulating Sézary
cells. Patients who experienced less than 50% clearance of skin and peripheral
blood disease were classified as nonresponders.
Photopheresis was discontinued if, despite photopheresis and treatment
with adjuvant agents, the disease progressed. In those patients who had a
complete remission, photopheresis therapy was tapered over several months
by increasing the interval between treatment cycles. In patients receiving
adjuvant therapy in combination with photopheresis, the medication dose was
maintained as the photopheresis was tapered and for a minimum of 6 months
after photopheresis therapy had been discontinued. The practice of tapering
treatment was based on our experience with 2 patients in whom a prompt relapse
occurred after photopheresis was discontinued abruptly.
DATA COLLECTION
All 47 patients with biopsy-proven CTCL who received photopheresis for
a minimum of 6 months, alone or in combination with adjuvant therapy, between
January 1985 and December 1998 at the Hospital of the University of Pennsylvania
were included in this series. This study was approved by the Committee on
Studies Involving Human Beings of the Hospital of the University of Pennsylvania.
Each patient's chart was reviewed by the cutaneous oncology fellow (K.R.S.)
to obtain historical data. All patients lost to follow-up were contacted by
telephone and interviewed to update our records. Follow-up was unavailable
for 3 patients. One patient was a woman with stage IIIB CTCL without circulating
Sézary cells who received 6 cycles of photopheresis as monotherapy
without a response. The second patient was a man with stage IB CTCL without
circulating Sézary cells who received 13 months of photopheresis. Interferon
alfa was added to his treatment regimen for the last 4 months of photopheresis.
Throughout his treatment, he remained a nonresponder. The last patient had
stage IIA disease with 70% circulating Sézary cells and received 21
cycles of photopheresis monotherapy. He had a complete response to therapy
and was alive and disease free at 105 months after starting photopheresis
but subsequently was lost to follow-up.
STATISTICAL ANALYSIS
Kaplan-Meier actuarial survival curves were calculated for the entire
treatment group and separately for patients with stages I and II disease vs
stages III and IV disease, and for patients receiving multimodality immunomodulatory
therapy or photopheresis monotherapy. Differences between the survival curves
were calculated using the Wilcoxon rank sum test.
We used t tests with Satterthwaite correction
for unequal variances to determine differences in WBC and CD4+/CD8+ ratios at the time of treatment initiation between patients who received
combination immunomodulatory therapy or photopheresis monotherapy. The t test without correction for unequal variances was used
for differences in initial lactic dehydrogenase (LDH) levels and percent Sézary
cells on buffy coat analysis in the 2 populations. A  2 contingency
table analysis was done to compare differences in disease stage and in the
number of patients with circulating Sézary cells at initiation of therapy
and to evaluate differences in clinical response rates for patients receiving
combination immunostimulatory therapy vs photopheresis monotherapy.
RESULTS
PATIENT CHARACTERISTICS
Forty-seven patients with histopathologically confirmed CTCL were treated
with at least 6 cycles of photopheresis between January 1985 and December
1998. Table 3 summarizes the baseline
characteristics of the patient population. Most patients had advanced disease
at the time treatment was initiated: 32 (68%) of the 47 patients had stage
III or IV disease; 42 (89%) of the 47 patients had peripheral blood involvement
as determined by the presence of more than 5% atypical cells detected by 1-µm
section analysis of peripheral blood buffy coats.
|
|
|
|
Table 3. Baseline Characteristics of 47 Patients Treated Between January
1985 and December 1998*
|
|
|
PATIENT CHARACTERISTICS BY THERAPY
Thirty-one (66%) of the 47 patients received combination biologic response
therapy whereas 16 (34%) received extracorporeal photopheresis monotherapy. Table 4 summarizes the baseline characteristics
of these 2 separate treatment populations. Differences between the 2 populations
were statistically significant for the mean CD4+/CD8+
ratio (P = .006). Differences in the percentage of
patients with greater than 5% circulating Sézary cells (P = .07) and for elevated WBC (P = .07) at
the time of treatment initiation were nearly statistically significant. Although
there seemed to be a trend toward higher Sézary counts seen on buffy
coat examination in patients who received combination therapy, there was no
statistically significant difference in this parameter between the 2 therapeutic
populations (P = .18). There were no significant
differences between the 2 treatment groups in mean LDH level (P = .99) or stage of disease at treatment initiation (P = .47).
|
|
|
|
Table 4. Baseline Characteristics by Therapeutic Group
|
|
|
THERAPEUTIC MODALITIES
All 47 patients received a minimum of 6 months of photopheresis therapy.
Thirty-one of the 47 patients received 1 or more adjuvant agents in combination
with photopheresis for at least 3 months. The most common adjuvant immunostimulatory
agent used in combination with photopheresis was interferon alfa (n = 30)
followed by systemic retinoids (n = 21) and sargramostim (n = 15) (Table 5). The types of retinoids used included
etretinate, acitretin, isotretinoin, and all-trans
retinoic acid. Some of the patients received focal treatment with topical
nitrogen mustard or carmustine (n = 35), topical steroids (n = 43), or
irradiation (n = 11). A small number of patients also received concomitant
PUVA (n = 5) or UV-B (n = 1) treatment.
|
|
|
|
Table 5. Types of Immunomodulatory Therapy Incorporated Into Patient
Care
|
|
|
RESPONSE TO THERAPY
Twelve (26%) of the 47 patients experienced a complete remission. Twenty-five
(53%) of the patients had a partial remission with at least a 50% reduction
of skin and peripheral blood disease. The overall positive response rate,
including complete and partial responders, was 37 (79%) of 47. Eight (17%)
of the patients were considered nonresponders. Only 2 patients (4%) experienced
progression of disease (Table 6).
The first patient had stage IVB disease with multiple cutaneous tumors, extensive
lymphadenopathy; an enlarged spleen; 7% Sézary cells on buffy coat
examination; normal WBC, LDH levels, and CD4+/CD8+ ratio;
and a clonal T-cell gene rearrangement in the peripheral blood by polymerase
chain reaction when photopheresis was started. He had been treated with topical
nitrogen mustard, topical carmustine, etretinate, PUVA, irradiation,
interferon alfa, and intralesional kenalog prior to starting photopheresis.
He received 7 cycles of photopheresis, 5 of which were combined with sargramostim.
The patient's condition progressively declined during that time. All immunomodulatory
therapies were discontinued, and the patient began therapy with systemic chemotherapy.
He died after receiving 3 months of chemotherapy. The second patient had stage
IIIB disease, also with multiple cutaneous nodules, no Sézary cells
on buffy coat examination, normal WBC, an LDH level of 626 U/L (normal,  620
U/L), and a CD4+/CD8+ ratio of 2.6 (normal, 2) when
photopheresis was initiated. She had received irradiation, multidrug
systemic chemotherapy, PUVA, topical nitrogen mustard, and systemic steroids
prior to starting photopheresis. She received 6 cycles of photopheresis monotherapy.
Her disease rapidly progressed and she was lost to follow-up soon after her
last treatment.
|
|
|
|
Table 6. Clinical Response to Therapy of All 47 Patients
|
|
|
Twenty-six (84%) of the 31 patients in the combination immunostimulatory
treatment group experienced either a complete or partial clinical response.
Six patients (20%) had a complete response, 20 (65%) had a partial response,
4 (13%) had no response, and 1 (3%) had progression of disease. Of the 16
patients who received photopheresis monotherapy, 12 (75%) had a positive response.
In this group, 6 (38%) were complete responders, 6 (38%) were partial responders,
3 (19%) did not respond to therapy, and 1 (6%) had progressive disease (Table 7). The differences in positive response
rates between the 2 therapeutic groups were not statistically significant
(P = .47). None of the patients experienced greater
than grade I toxic effects, according to the common toxicity criteria of the
National Cancer Institute.
|
|
|
|
Table 7. Clinical Response by Therapeutic Group*
|
|
|
PATIENT SURVIVAL
The median survival of all 47 patients calculated from the first treatment
date using the Kaplan-Meier actuarial survival curve was 74 months (6.2 years)
(Figure 1). Most (68%) of the patients
had stage III or IV CTCL.
|
|
|
|
Figure 1. Survival of all 47 patients treated
between January 1985 and December 1998. The median survival from initiation
of therapy was 74 months (6.2 years).
|
|
|
Kaplan-Meier survival curves were also calculated to compare survival
between patients with early-stage disease (stages I and II) and advanced disease
(stages III and IV) (Figure 2).
Patients with late-stage disease experienced a median survival of 55 months
(4.6 years), whereas patients with early stage disease had a median survival
of 92 months (7.7 years). The difference in survival between these 2 groups
was statistically significant (P = .03).
|
|
|
|
Figure 2. Survival of patients with stages
I and II cutaneous T-cell lymphoma (n = 15) vs stages III and IV disease (n
= 32). Median survival times were 92 months (7.7 years) and 55 months (4.6
years), respectively (P = .03).
|
|
|
To evaluate for a possible difference in survival between patients treated
with multimodality biologic response therapy and those who received extracorporeal
photopheresis monotherapy, we calculated survival curves separately for the
2 groups (Figure 3). The median
survival for the patients undergoing combination therapy was 74 months (6.2
years), whereas the median survival for the monotherapy group was 66 months
(5.5 years). Survival differences for the 2 treatment groups were not statistically
significant (P = .51).
|
|
|
|
Figure 3. Survival of patients treated with
combination immunomodulatory therapy vs photopheresis monotherapy. Median
survival times were 74 months (6.2 years) and 66 months (5.5 years), respectively
(P = .51).
|
|
|
COMMENT
Extracorporeal photopheresis is an established and effective treatment
for advanced CTCL. Several groups have reported positive response rates ranging
from 50% to 80% for patients with advanced-stage CTCL.20-22,25-27
Photopheresis may also prolong patient survival. Gottleib et al20
reported a median survival of longer than 100 months from the time of diagnosis
in patients with advanced-stage disease and peripheral blood involvement treated
with a minimum of 6 months of photopheresis compared with a median survival
of 30 to 40 months in historical controls.
Although the precise mechanism of action of photopheresis has not been
determined, exposure of leukocytes to UV-A following uptake of 8-methoxypsoralen
results in cross-linking of DNA and eventual apoptotic cell death.16, 28 Murine skin transplantation models
indicate that the treated leukocytes are altered in some fashion such that,
when reinfused, a specific anticlonotypic immune response directed toward
the pathogenic cells develops.29 Therefore,
the overall integrity of the immune response is believed to be a critical
factor for patient responsiveness to photopheresis monotherapy.
Interferon alfa is a potent biologic agent that has powerful antiproliferative,
immunostimulatory, and differentiation-inducing activities. Clinical trials
have shown response rates of 50% to 80% in patients with CTCL receiving systemic
interferon alfa.30-31 It also
exerts substantial immune augmentative effects on cytotoxic T-cell function
and can reverse cytokine and immune abnormalities in Sézary syndrome.32 Administration of sargramostim may enhance antigen
presentation and lead to an augmented antitumor response to the apoptotic
T cells, and systemic retinoids can induce T-helper type 1 cytokine production
by peripheral blood mononuclear cells in vitro.33
Because little is known about the use of multiple immunomodulatory agents
to treat patients with advanced CTCL, our purpose was to determine the efficacy
of this therapeutic approach.
Our previous experience formed the basis for the development of a clinical
profile of those CTCL patients most likely to respond to extracorporeal photopheresis
monotherapy. These clinical criteria include the presence of modest numbers
of peripheral blood Sézary cells (10%-20% of mononuclear cells); short
duration of disease (less than 2 years); normal or nearly normal numbers of
cytotoxic T lymphocytes with nearly normal CD4+/CD8+
ratios; normal or modestly elevated WBC; no history of intensive chemotherapy;
and absence of bulky lymphadenopathy or overt visceral disease.20, 34
Using these criteria as a guideline, the patients who received combination
biologic response therapy in the present study had a worse prognosis at the
time of treatment initiation than those who received photopheresis monotherapy,
as evidenced by higher CD4+/CD8+ ratios, higher WBCs,
a higher percentage of patients with peripheral blood involvement by Sézary
cells, and higher percentages of circulating Sézary cells than those
who received photopheresis monotherapy. Although the differences in some of
these parameters were not statistically significant, a 4-fold increase in
sample size would be needed to achieve an 80% chance of detecting statistical
significance. Therefore, we consider the finding of a higher number of poor
prognostic factors in the population receiving multimodality immunostimulatory
therapy clinically relevant.
For all 47 patients, the overall positive response rate, including complete
and partial responders, was 79%. The positive response rate for the 31 patients
who received combination therapy was 84%. Although some groups have reported
response rates of 76% to 80% with photopheresis monotherapy, these rates were
achieved in patient populations with more limited skin disease and/or normal
WBCs and CD4+/CD8+ ratios.20, 25
As most of our patients had multiple poor prognostic factors at the time of
treatment initiation, it seems that multimodality biologic response therapy
enhances clinical response in patients with an expected worse outcome. In
addition, the median survival in our patient population, 68% of whom had stage
III or IV CTCL, was 6.2 years. This represents a marked improvement in survival
over historical controls, who had median survival times of 4.6 and 1.1 years
for stages III and IV, respectively.6 Unfortunately,
patients with extensive cutaneous tumors experienced poor responses to photopheresis
alone or in combination with other immunostimulatory agents.
Survival curves were also calculated to compare survival between patients
with limited skin disease and extensive disease. Patients with stages III
and IV disease experienced a median survival of 4.6 years, whereas patients
with early-stage disease had a median survival of 7.7 years. Nearly all of
the patients in our study had peripheral blood involvement, which confers
a worse prognosis in any stage of disease. Therefore, our patients with widespread
disease experienced a marked improvement in survival over the previously reported
median survival of 2.6 years for patients with erythrodermic CTCL and peripheral
blood involvement who received PUVA, radiation therapy, or chemotherapy, alone
or in combination.6 Additionally, Kim et al6 have found that age at presentation of 65 years or
older, clinical stage of IV, and B stage of 1 are associated with poor prognosis.6 In their study, patients receiving traditional nonimmunomodulatory
therapy were categorized based on the number of poor prognostic factors present
at the time of diagnosis. The median survival was 1.5 years for patients who
presented with 2 or 3 poor prognostic factors, and 3.7 years for those who
presented with 1 factor.6 The average age of
presentation for our patients was 62 years, and nearly all had peripheral
blood involvement, independent of tumor stage. Thus, since most of our patients
had 2 poor prognostic factors independent of tumor stage, treatment with combination
biologic response therapy markedly improved survival in all our patients over
that of historical controls with similar factors.
We compared survival between patients treated with multimodality immunostimulatory
therapy and those who received extracorporeal photopheresis monotherapy to
evaluate for a possible improvement in outcome with the addition of immunomodulatory
agents. The median survival for the patients undergoing combination therapy
was 6.2 years, whereas the median survival for the monotherapy group was 5.5
years. Although neither the differences between the median survival values
nor the differences between the 2 survival curves were statistically significant,
there may be a trend toward longer survival in patients treated with combination
immunomodulatory therapy. Importantly, the patients who received combination
immunomodulatory therapy had a worse prognosis at initiation of therapy. Therefore,
the findings presented here suggest that multimodality biologic response therapy
may be more effective for patients with multiple poor prognostic factors than
extracorporeal photopheresis monotherapy.
The review of our experience with combination immunomodulatory therapy
suggests that patients with advanced CTCL receiving this therapy experience
high clinical response rates and prolonged survival compared with historical
controls. In comparison with patients with less severe disease treated with
photopheresis monotherapy, patients with multiple poor prognostic factors
experience equal or improved clinical outcomes when treated with multimodality
immunostimulatory therapy. Although further investigation is needed to better
establish the effectiveness of multimodality biologic response therapy for
the treatment of cutaneous T-cell lymphoma, the results of our study suggest
that it should be considered first-line therapy for patients with advanced-stage
disease and multiple poor prognostic variables.
AUTHOR INFORMATION
Accepted for publication November 28, 2001.
This study was supported by grants CA80108, CA81022, and MO1RR00040-29
from the National Institutes of Health, Bethesda, Md, and a grant from the
Leukemia and Lymphoma Society, White Plains, NY.
This work received the Nelson Paul Anderson Memorial Award of the 2000
Pacific Dermatologic Association, Victoria, British Columbia, and the Johnson-Beerman
Award of the 2001 Section on Dermatology, College of Physicians of Philadelphia,
Philadelphia, Pa.
Corresponding author and reprints: Alain H. Rook, MD, Department
of Dermatology, Hospital of the University of Pennsylvania, 2 Rhoads Pavilion,
3600 Spruce St, Philadelphia, PA 19104-4283 (e-mail: arook{at}mail.med.upenn.edu).
From the Department of Dermatology and the General Clinical Research
Center of the Hospital of the University of Pennsylvania, Philadelphia.
REFERENCES
| |
1. Murphy GF. Cutaneous T-cell lymphoma. Adv Pathol. 1988;1:131-156.
2. Lutzner M, Edelson R, Schein P, Green I, Kirkpatrick C, Ahmed A. Cutaneous T-cell lymphomas: the Sézary syndrome, mycosis fungoides
and related disorders. Ann Intern Med. 1975;83:534-552.
3. Hoppe RT, Wood GS, Abel EA. Mycosis fungoides and the Sézary syndrome: pathology, staging,
and treatment. Curr Probl Cancer. 1990;14:293-371.
PUBMED
4. Kuzel TM, Roenigk HH, Rosen ST. Mycosis fungoides and the Sézary syndrome: a review of the pathogenesis,
diagnosis, and therapy. J Clin Oncol. 1991;9:1298-1313.
ABSTRACT
5. Sézary A, Bouvrain Y. Erythroderma avec presence de cellules monstrueses dans la derme el
le sang circulant. Bull Soc Fr Dermatol Syphil. 1938;45:357-368.
6. Kim YH, Bishop K, Varghese A, Hoppe RT. Prognostic factors in erythrodermic mycosis fungoides and the Sézary
syndrome. Arch Dermatol. 1995;131:1003-1008.
FREE FULL TEXT
7. Green SB, Byar DP, Lamberg SI. Prognostic variables in mycosis fungoides. Cancer. 1981;47:2671-2677.
FULL TEXT
|
ISI
| PUBMED
8. Lamberg SI, Green SB, Byar DP, et al. Clinical staging for cutaneous T-cell lymphoma. Ann Intern Med. 1984;100:187-192.
9. Weinstock MA, Horm JW. Population-based estimate of survival and determinants of prognosis
in patients with mycosis fungoides. Cancer. 1988;62:1658-1661.
FULL TEXT
|
ISI
| PUBMED
10. Sausville EA, Eddy JL, Makuch RW, et al. Histopathologic staging at initial diagnosis of mycosis fungoides and
the Sézary syndrome: definition of three distinctive prognostic groups. Ann Intern Med. 1988;109:372-382.
11. Marti RM, Estrach T, Reverter JC, Mascaro HM. Prognostic clinicopathologic factors in cutaneous T-cell lymphoma. Arch Dermatol. 1991;127:1511-1516.
FREE FULL TEXT
12. Kim YH, Jensen RA, Watanabe GL, Varghese A, Hoppe RT. Clinical stage IA (limited patch and plaque) mycosis fungoides: a long-term
outcome analysis. Arch Dermatol. 1996;132:1309-1313.
FREE FULL TEXT
13. Dummer R, Heald PW, Nestle FO, et al. Sézary syndrome T-cell clones display T-helper 2 cytokines and
express the accessory factor-1 (interferon gamma receptor beta-chain). Blood. 1996;88:1383-1389.
FREE FULL TEXT
14. Vowels BR, Cassin M, Vonderheid EC, Rook AH. Aberrant cytokine production by Sézary syndrome patients: cytokine
secretion pattern resembles murine Th2 cells. J Invest Dermatol. 1992;99:90-94.
FULL TEXT
|
ISI
| PUBMED
15. Berger CL, Wang N, Christensen I, Longley J, Heald P, Edelson RL. The immune response to class I–associated tumor-specific cutaneous
T-cell lymphoma antigens. J Invest Dermatol. 1996;107:392-397.
FULL TEXT
|
ISI
| PUBMED
16. Yoo EK, Rook AH, Elenitsas R, Gasparro FP, Vowels BR. Apoptosis induction by ultraviolet light A and photochemotherapy in
cutaneous T-cell lymphoma: relevance to mechanism of action. J Invest Dermatol. 1996;107:235-242.
FULL TEXT
|
ISI
| PUBMED
17. Vowels BR, Cassin M, Boufal MH, Walsh LJ, Rook AH. Extracorporeal photochemotherapy induces the production of tumor necrosis
factor-alpha by monocytes: implication for the treatment of cutaneous T-cell
lymphoma and systemic sclerosis. J Invest Dermatol. 1992;98:686-692.
FULL TEXT
|
ISI
| PUBMED
18. Moor ACE, Schmitt IM, Beijersbergen van Henegouwen GM, Chimenti S, Edelson RL, Gasparro FP. Treatment with 8-MOP and UVA enhances MHC class I synthesis in RMA
cells: preliminary results. J Photochem Photobiol B. 1995;29:193-198.
FULL TEXT
| PUBMED
19. Fimiani M, Rubegni P, Pimpinelli N, Mori M, De Aloe G, Andreassi L. Extracorporeal photochemotherapy induces a significant increase in
CD36+ circulating monocytes in patients with mycosis fungoides. Dermatology. 1997;194:107-110.
ISI
| PUBMED
20. Gottleib SL, Wolfe JT, Fox FE, et al. Treatment of cutaneous T-cell lymphoma with extracorporeal photopheresis
monotherapy and in combination with recombinant interferon alpha: a 10-year
experience at a single institution. J Am Acad Dermatol. 1996;35:946-957.
FULL TEXT
|
ISI
| PUBMED
21. Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy:
preliminary results. N Engl J Med. 1987;316:297-303.
ABSTRACT
22. Duvic M, Hester JP, Lemak NA. Photopheresis therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol. 1996;35:573-579.
FULL TEXT
|
ISI
| PUBMED
23. Rook AH, Berkson MH, Vowels BR. Extracorporeal photopheresis: principles and practice. In: Lim HW, Soter NA, eds. Clinical Photomedicine. New York, NY: Marcel Dekker; 1993:347-360.
24. Bunn PA Jr, Lamberg SI. Report on the Committee on Staging and Classification of cutaneous
T-cell lymphomas. Cancer Treat Rep. 1979;63:725-728.
ISI
| PUBMED
25. Jiang SB, Dietz SB, Kim M, Lim HW. Extracorporeal photochemotherapy for cutaneous T-cell lymphoma: a 9.7
year experience. Photodermatol Photoimmunol Photomed. 1999;15:161-165.
ISI
| PUBMED
26. Zic JA, Stricklin GP, Greer JP, et al. Long-term follow-up of patients with cutaneous T-cell lymphoma treated
with extracorporeal photochemotherapy. J Am Acad Dermatol. 1996;35:935-945.
FULL TEXT
|
ISI
| PUBMED
27. Prinz B, Behrens W, Holzle E, Plewig G. Extracorporeal photopheresis for the treatment of cutaneous T-cell
lymphoma: the Dusseldorf and Munich experience. Arch Dermatol Res. 1995;287:621-626.
FULL TEXT
|
ISI
| PUBMED
28. Gasparro FP, Dall'Amico R, Goldminz D, Simmons E, Weingold D. Molecular aspects of extracorporeal photochemotherapy. Yale J Biol Med. 1989;62:579-593.
ISI
| PUBMED
29. Perez M, Edelson R, Laroche L, Berger C. Inhibition of antiskin allograft immunity by infusions with syngeneic
photoinactivated effector lymphocytes. J Invest Dermatol. 1989;92:669-676.
FULL TEXT
|
ISI
| PUBMED
30. Olsen EA, Rosen ST, Vollmer RT, et al. Interferon alpha-2a in the treatment of cutaneous T-cell lymphoma. J Am Acad Dermatol. 1989;20:395-407.
ISI
| PUBMED
31. Olsen EA, Bunn PA. Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. 1995;9:1089-1107.
ISI
| PUBMED
32. Rook AH, Kubin M, Cassin M, et al. IL-12 reverses cytokine and immune abnormalities in Sézary syndrome. J Immunol. 1995;154:1491-1498.
ABSTRACT
33. Fox FE, Kubin M, Cassin M, et al. Retinoids synergize with interleukin-2 to augment IFN- and interleukin
12 production by human peripheral blood mononuclear cells. J Interferon Cytokine Res. 1999;19:407-415.
FULL TEXT
|
ISI
| PUBMED
34. Rook AH, Suchin KR, Kao DM, et al. Photopheresis: clinical applications and mechanism of action. J Investig Dermatol Symp Proc. 1999;4:85-90.
ISI
| PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Primary Cutaneous T-Cell Lymphomas
Rosen and Querfeld
ASH Education Book 2006;2006:323-330.
ABSTRACT
| FULL TEXT
The Addition of Interferon Gamma to Oral Bexarotene Therapy With Photopheresis for Sezary Syndrome
McGinnis et al.
Arch Dermatol 2005;141:1176-1178.
FULL TEXT
Low-Dose Bexarotene and Low-Dose Interferon Alfa-2b for Adult T-Cell Leukemia/Lymphoma Associated With Human T-Lymphotropic Virus 1
Richardson et al.
Arch Dermatol 2005;141:301-304.
FULL TEXT
Enhancement of the host immune responses in cutaneous T-cell lymphoma by CpG oligodeoxynucleotides and IL-15
Wysocka et al.
Blood 2004;104:4142-4149.
ABSTRACT
| FULL TEXT
The Pathogenesis of Mycosis Fungoides
Girardi et al.
NEJM 2004;350:1978-1988.
FULL TEXT
Psoralen Plus Long-Wave UV-A (PUVA) and Bexarotene Therapy: An Effective and Synergistic Combined Adjunct to Therapy for Patients With Advanced Cutaneous T-Cell Lymphoma
McGinnis et al.
Arch Dermatol 2003;139:771-775.
ABSTRACT
| FULL TEXT
|
