 |
|
Circulating CD4+CD7- Lymphocyte Burden and Rapidity of Response
Predictors of Outcome in the Treatment of Sézary Syndrome and Erythrodermic Mycosis Fungoides With Extracorporeal Photopheresis
Seth R. Stevens, MD;
Elma D. Baron, MD;
Susan Masten, RN;
Kevin D. Cooper, MD
Arch Dermatol. 2002;138:1347-1350.
ABSTRACT
| |
Background Extracorporeal photopheresis (ECP) is an effective treatment for cutaneous
T-cell lymphoma. Controversy has arisen regarding its ability to improve survival
rates in Sézary syndrome (SS). We describe our experience with ECP
in the treatment of SS and erythrodermic mycosis fungoides, with particular
emphasis on early predictors of long-term outcome.
Observations We included 17 patients (15 with SS and 2 with erythrodermic mycosis
fungoides) who received ECP as initial treatment. Four of these patients were
moribund on presentation (Eastern Cooperative Oncology Group Performance Status
score, 4) and underwent only 1 to 2 cycles of ECP. The median survival was
56 months for the 11 patients with SS and an Eastern Cooperative Oncology
Group Performance Status score of less than 4. If all 15 patients with SS
are considered, median survival was 34 months. Response after 5 months of
ECP correlated with long-term survival. A low number (<6.0 x103/µL) of circulating CD4+CD7- lymphocytes
correlated with response after 5 months of ECP.
Conclusions Extracorporeal photopheresis is a safe, effective, and well-tolerated
treatment for erythrodermic mycosis fungoides and SS. Low numbers of CD4+CD7- cells in the circulation and a positive response
after 5 months of therapy predicted long-term survival. Moribund patients
are much less likely to benefit from ECP.
INTRODUCTION
SÉZARY SYNDROME (SS) is the leukemic variant of cutaneous T-cell
lymphoma (CTCL) characterized by erythroderma, lymphadenopathy, and the presence
of atypical lymphocytes with cerebriform nuclei (Sézary cells) in the
circulation. This syndrome carries a poor prognosis, with a median survival
time of 31 months and a 5-year survival rate of 33.5%.1 A
multivariate analysis of 51 SS cases identified the following to be poor prognostic
factors: (1) the presence of cytoplasmic inclusions on results of periodic
acid–Schiff staining, (2) a CD7- phenotype, and (3)
the presence of large (>15 µm) Sézary cells.1 Another
study that analyzed data from 106 patients with SS or erythrodermic mycosis
fungoides showed that patient age at presentation, overall stage, and peripheral
blood involvement were significant prognostic factors.2
Extracorporeal photopheresis (ECP) has been a standard treatment for
CTCL and has been specifically recommended as first-line treatment for SS
on the basis of multicenter reports indicating a prolonged median survival
among ECP-treated patients with SS.3 The ratio
of peripheral blood CD4/CD8 cell count, time from CTCL diagnosis to initiation
of ECP, number of photopheresis sessions, and response at 6 to 8 months of
treatment have been shown to be of predictive value with regard to long-term
outcome.4-7 A
higher baseline lymphocyte count and a higher Sézary cell count as
a percentage of total white blood cell count have also been associated with
a positive response after 6 months of ECP.8 However,
the absence of randomized controlled trials, the small numbers of patients
described in case series, and the lack of rigorous entry criteria such as
T-cell receptor gene rearrangement (TCGR) data have resulted in controversy
regarding the benefits of ECP.9-10
The purpose of this study is to describe our experience with ECP as
first-line treatment for SS and erythrodermic mycosis fungoides, with a particular
focus on early predictors of outcome.
PATIENTS AND METHODS
The study was approved by the Institutional Review Board of the University
of Michigan Medical Center, Ann Arbor. From August 1, 1987, through June 20,
1994, a total of 18 patients with the diagnosis of SS (n = 16) or erythrodermic
mycosis fungoides (n = 2) entered the ECP program of the Cutaneous Lymphoma
Clinic at the University of Michigan. The diagnosis and stage (as determined
by the criteria of the CTCL Cooperative Group11)
were established by results of physical examination; histology; immunophenotypic
analysis of blood and skin biopsy specimens; TCGR analyses (by means of Southern
blotting of skin and blood specimens); peripheral blood smear review; chest
x-ray computed tomographic scans of the chest, abdomen, and pelvis; cytologic
or histologic review of suspicious lymph nodes; routine complete blood cell
counts; and chemistry panels as previously reported.12 Patients
likewise underwent screening via serologic tests for human T-lymphotropic
virus 1 and human immunodeficiency virus. One patient with SS transferred
to another institution after only 2 months of treatment and was therefore
excluded from further analysis. Data are reported through December 31, 2000.
A UV-A radiation system (UVAR System; Therakos, Inc, Exton, Pa) was
used. Patients received 0.6 mg/kg of methoxsalen 90 to 120 minutes before
phlebotomy. Approximately 6 cycles of discontinuous centrifugation were required
to obtain the requisite 240 mL of leukocyte-enriched blood, which was then
combined with 300 mL of plasma and 200 mL of sterile isotonic sodium chloride
solution. This mixture was then exposed to the UV-A (320-400 nm) light source
for 1.5 to 2.0 hours and reinfused into the patient. This procedure was performed
on 2 consecutive days twice monthly for the first 2 months, and monthly thereafter.
Patients who maintained a complete remission for 1 year continued treatment
every other month.
We used Kaplan-Meier analysis and defined outcome as survival. Intervening
outcomes at 5 months of ECP were defined as follows: complete remission, no
evidence of disease on results of physical examination, computed tomographic
scans, blood examination for circulating Sézary cells, or abnormal
immunophenotype by means of flow cytometry; partial remission, greater than
50% reduction in the skin severity score.13 Responders
are those who achieved a partial or a complete remission, whereas stable disease
indicated less than a 50% reduction in the skin severity score. Data were
analyzed by  2 and 2-tailed Fisher exact test.
OBSERVATIONS
Patient characteristics are summarized in Table 1. Although 5 patients in the SS group did not have 100% total
body surface area involvement as reflected by their T stage, they all had
severe erythema over at least 90% of their total body surface area. Significant
blood involvement was documented in the 15 patients with SS; 14 showed positive
findings for clonality in the peripheral blood as shown by results of TCGR
analysis, and 1 had a CD4+CD7- population consisting
of 80% circulating T cells. Four patients were moribund at the time of enrollment,
with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score
of 4.14 These patients received only 1 or 2
cycles of ECP and died within the first 2 months of therapy. The median survival
for patients with an ECOG PS score of less than 4 was 56 months (Figure 1). When the moribund patients were
included in the analysis, median survival of all 15 shifted to 34 months (Figure 1).
|
|
|
|
Table 1. Patient Characteristics*
|
|
|
|
|
|
|
Survival of patients with Sézary syndrome (SS) receiving extracorporeal
photopheresis (ECP) by length of treatment. The solid line indicates the survival
plot of patients with SS and an Eastern Cooperative Oncology Group Performance
Status (ECOG PS) score of less than 4 (n = 11); dashed line, patients with
SS regardless of ECOG PS score (n = 15); crosses on each plot, the number
of months of ECP for each of the 4 subjects who were still being followed
up as of December 2000.
|
|
|
Three subpopulations emerged among the study patients. Patients in the
first group, as mentioned above, were in the end stages of aggressive disease
and died early; the second group had recalcitrant disease with an indolent
course and died 2 to 3 years after initiation of ECP; and the third group
showed a rapid response to ECP (within 5 months) and survived longer than
3 years. Most of the third group are current survivors (>5 years). To confirm
whether early response correlated with long-term outcome, the patient status
after 5 months of ECP was analyzed and compared with survival. Results of
this analysis showed that 5 of 9 five-month responders are long-term survivors
(ie, >5 years). In contrast, none of the 8 subjects whose response was less
than 50% after 5 months of ECP survived beyond 37 months from initiation of
ECP. The number of circulating CD4+CD7- lymphocytes
was then compared with status at 5 months (Table 2). Patients who had fewer (<6.0 x103/µL)
CD4+CD7- lymphocytes were more likely to have
achieved a response after 5 months of ECP (P = .046).
The presence or absence of nodal disease was shown to be of significance when 2 analysis was used (P = .03). However, using
the Fisher exact test, which more accurately accommodates small cell sizes,
this variable did not demonstrate statistically significant predictive value
(P = .10). Similarly, the following variables were
not found to be predictive of outcome in our patients: age, sex, time from
onset of skin symptoms to initiation of ECP, stage of disease, skin severity
score, and complications during therapy (data not shown).
|
|
|
|
Table 2. Status at 5 Months of ECP*
|
|
|
The 2 patients with erythrodermic mycosis fungoides were not included
in the survival analysis. One of them is in complete remission, whereas the
other died after 39 months of ECP, secondary to chronic obstructive pulmonary
disease.
No major adverse effects were noted during the course of ECP. Two patients
with preexisting cardiac problems experienced transient pulmonary edema, which
responded to diuresis. Minor problems related to the intravenous access site,
such as bleeding and poor wound healing, were managed appropriately.
COMMENT
Controversy exists regarding the efficacy of ECP in SS. We believe the
appropriate patients to assess ECP efficacy in SS are those with involvement
of the skin and blood. We accept morphologic, phenotypic, or molecular biological
evidence of blood involvement. We do not view ECP as salvage therapy; therefore,
we do not believe that including results from moribund patients (ECOG PS score,
4) is appropriate. In the present study, 11 patients had significant skin
and blood involvement and an ECOG PS score of less than 4, and their median
survival was 56 months (Figure 1).
Although many reports support the notion of benefit of ECP in patients
with SS, a more recent report questions these findings.9 The
authors suggested that the presence of a demonstrable T-cell clone, determined
by Southern blotting, should define SS. Using this definition, they found
a 39-month survival. A more recent study by these authors and others suggests
benefit of ECP for patients with SS.8 The ECOG
PS scores of the patients were not indicated. Applying this criterion to our
patients (ie, including only patients with positive findings for TCGR and
disregarding performance status) similarly yields a median survival of 31
months. However, we believe that the benefit of ECP accrues over months of
treatment. Other studies on ECP have also emphasized the need for a reasonable
number of treatments before its efficacy can be evaluated.15-16 Thus,
exclusion of moribund patients is appropriate. Our median survival for patients
with positive findings for TCGR in the blood, with ECOG PS of less than 4,
is 47 months. However, because false-negative results of gene rearrangement
tests have been found,17 we do not require
this test result to be positive to diagnose SS. Our patient with negative
findings for TCGR was more likely to have had a false-negative finding, particularly
given the large number of circulating CD4+CD7- cells
and the Sézary cell count of greater than 15%.
Our study population could be divided between those who demonstrated
a response within 5 months of ECP (n = 9) and those who died before or did
not show any response after 5 months of treatment (n = 8). Results showed
that status at 5 months is a surrogate marker for long-term outcome, which
is similar to the findings of Zic et al.6 Adding
an extra treatment course for each of the first 2 months, as we have done,
might reduce the response time, or might be an expected variation given small
sample sizes.
The dominant T-cell clone in CTCL is believed to be of the CD4+CD7- phenotype.18 To
our knowledge, the CD4+CD7- level is a variable
that has never been evaluated in previous investigations involving the use
of ECP for SS. Nevertheless, the CD7- phenotype has been
reported to be correlated with poor prognosis.1 The
exact reason for this is unknown. However, because CD7+ cells have
been found to enhance humoral and cell-mediated immunity, it has been speculated
that a high proportion of CD7- cells could result in reduced
or impaired antitumor immune responses.1 Our
finding that patients with a higher burden of CD4+CD7- cells have a worse prognosis supports this concept. The increase in
CD4+CD7- cells in patients with CTCL has also
been associated with altered expression of certain activation-, differentiation-,
and homing-related antigens and with the presence of a specific subset of
circulating malignant cells (CD3dim [ie, having diminished intensity
of CD3 expression] or large-sized lymphoblasts) among patients with SS, all
of which are associated with more aggressive disease.18
The presence or absence of nodal disease surprisingly was not found
to be a significant predictor of outcome based on results of the Fisher exact
test. Results of 2 analysis, however, suggested that this
variable might have a predictive value. A larger sample size is necessary
to confirm the value of these tests.
CONCLUSIONS
In our cohort of patients, we confirmed that early response is a predictor
of survival in ECP-treated patients with SS. We also found that high levels
of circulating CD4+CD7- cells are a poor prognostic
indicator and that moribund patients (ECOG PS score, 4) are much less likely
to respond to ECP. These findings are consistent with the notion that to respond,
patients must have enough immunologic reserve to be augmented by ECP. Similarly,
the patients must survive long enough ( 3 months) to generate ECP-induced
immune modulation. We believe that appropriate patient selection for ECP is
critical for success and suspect that differences in reported outcomes derive
in part from such patient selection.
AUTHOR INFORMATION
Accepted for publication March 26, 2002.
Corresponding author: Seth R. Stevens, MD, Department of Dermatology,
Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106 (e-mail: srs{at}po.cwru.edu).
From the Departments of Dermatology, University Hospitals of Cleveland
Research Institute/Case Western Reserve University (Drs Stevens, Baron, and
Cooper) and the Louis Stokes Veterans Affairs Medical Center (Dr Stevens),
Cleveland, Ohio; and the Cutaneous Lymphoma Program, Immunodermatology Unit,
University of Michigan Medical Center, Ann Arbor (Ms Masten).
REFERENCES
| |
1. Bernengo MG, Quaglino P, Novelli M, et al. Prognostic factors in Sezary syndrome: a multivariate analysis of clinical,
haematological and immunological features. Ann Oncol. 1998;9:857-863.
FREE FULL TEXT
2. 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
3. Lim HW, Edelson RL. Photopheresis for the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. 1995;9:1117-1126.
ISI
| PUBMED
4. Heald P, Rook A, Perez M, et al. Treatment of erythrodermic cutaneous T-cell lymphoma with extracorporeal
photochemotherapy. J Am Acad Dermatol. 1992;27:427-433.
ISI
| PUBMED
5. Zic J, Arzubiaga C, Salhany KE, et al. Extracorporeal photopheresis for the treatment of cutaneous T-cell
lymphoma. J Am Acad Dermatol. 1992;27:729-736.
ISI
| PUBMED
6. 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
7. Rook AH, Gottlieb SL, Wolfe JT, et al. Pathogenesis of cutaneous T-cell lymphoma: implications for the use
of recombinant cytokines and photopheresis. Clin Exp Immunol. 1997;107(suppl 1):16-20.
8. Evans AV, Wood BP, Scarisbrick JJ, et al. Extracorporeal photopheresis in Sezary syndrome: hematologic parameters
as predictors of response. Blood. 2001;98:1298-1301.
FREE FULL TEXT
9. Fraser-Andrews E, Seed P, Whittaker S, Russell-Jones R. Extracorporeal photopheresis in Sézary syndrome: no significant
effect in the survival of 44 patients with a peripheral blood T-cell clone. Arch Dermatol. 1998;134:1001-1005.
FREE FULL TEXT
10. Stevens SR, Bowen GM, Duvic M, et al. Effectiveness of photopheresis in Sezary syndrome [letter]. Arch Dermatol. 1999;135:995-997.
FREE FULL TEXT
11. Terhune M, Oberhelman L, Strawderman M, et al. A logistic regression model to improve and standardize the diagnosis
of mycosis fungoides. Presented as a workshop at: International Consensus Conference: Staging
and Treatment Recommendations for CTCL; October 1-2, 1994; Boston, Mass.
12. Bunn PA, Lamberg SI. Report of Committee on Staging and Classification of Cutaneous T-Cell
Lymphomas. Cancer Treat Rep. 1979;63:725-728.
ISI
| PUBMED
13. Stevens SR, Ke MS, Parry EJ, Mark J, Cooper KD. Quantifying skin disease burden in mycosis fungoides–type cutaneous
T-cell lymphoma: the severity-weighted assessment tool (SWAT). Arch Dermatol. 2002;138:42-48.
FREE FULL TEXT
14. Sorensen JB, Klee M, Palshof T, Hansen HH. Performance status assessment in cancer patients: an inter-observer
variability study. Br J Cancer. 1993;67:773-775.
ISI
| PUBMED
15. 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
16. 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
17. Weinberg JM, Jaworsky C, Benoit BM, Telegan B, Rook AH, Lessin SR. The clonal nature of circulating Sezary cells. Blood. 1995;86:4257-4262. [published correction appears in Blood. 1996;87:4923].
FREE FULL TEXT
18. Scala E, Russo G, Cadoni S, et al. Skewed expression of activation, differentiation and homing-related
antigens in circulating cells from patients with cutaneous T cell lymphoma
associated with CD7-T helper lymphocytes expansion. J Invest Dermatol. 1999;113:622-627.
FULL TEXT
|
ISI
| PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Monoclonal T-Cell Dyscrasia of Undetermined Significance Associated With Recalcitrant Erythroderma
Gniadecki and Lukowsky
Arch Dermatol 2005;141:361-367.
ABSTRACT
| FULL TEXT
|
