Therapy Treatment of erythrodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy P. Heald, MD,a A. Rook, MD,b M. Perez, MD,a B. Wintroub, MD,c R. Knobler, MD,d B. Jegasothy, MD,e F. Gasparro, PhD,a C. Berger, PhD/ and R. Edelson, MDa New Haven, Connecticut; Philadelphia and Pittsburgh, Pennsylvania; San Francisco, California; Vienna, Austria; and New York, New York Background: This original cohort of patients with erythrodermic cutaneous T-cell lymphoma (CTCL) was reported to have clinical improvement with photopheresis during the 12 months of the original study. No long-term follow-up data have been available to examine the impact of this therapy on the disease. Objective: Our purpose was to provide long-term follow-up on the original 29 erythrodermic CTCL patients treated with photopheresis and to compare these results with historical controls. Methods: Files of patients from the original photopheresis study centers were reviewed and their current status was documented. Results: The median survival of the treated patients was 60.33 months from the date of diagnosis and 47.9 months from the date of the start of photopheresis therapy. A complete remission has been maintained in four of the six patients who achieved complete responses in the original study. The best responses were seen in patients with a lower CD4jCD8 ratio in the peripheral blood at the start of therapy. Conclusion: Photopheresis can influence the natural history of erythrodermic CTCL by inducing remissions and prolonging survival with minimal toxicity. (J AM ACAD DERMATOL 1992;27:427-33.)
Cutaneous T -cell lymphoma (CTCL) is a malignancy of rnature T cells of the helper phenotype that initially invade the skin. I Clinical evolution of CTCL to widespread skin erythroderma, overt lymph node infiltration, or skin tumor development is associated with a poor prognosis. 2-6 A tumor registry survey suggested that the overall outcome of CTCL may not be affected by therapeutic advances. 7 A recent randomized trial supported that suggestion by finding that the overall survival of CTCL was not altered by conventional radio/chemotherapy despite palliative effects. 6 Extracorporeal photochemotherapy (photopheresis) has been shown in a multicenter study to decrease skin involvement in the study group of 29 patients with erythrodermic CTCL. 8 The potential From the Departments of Dermatology, Yale University School of Medicine, New Havena ; University of Pennsylvania, Philadelphia b; University of California, San Franciscoc; University of Vienna, Austriad; University of Pittsburghe; and Columbia College of Physicians and Surgeons, New YorkJ Reprint requests; Peter Heald, MD, 500 LCI, 333 Cedar St., New Haven, CT 06510.
16(1/37438
significance of those findings was suggested by studies in rodents indicating that reinfusion of similarly treated pathogenic T cells produces disease-modifying immunologic effects. 9- 11 In clinical photopheresis or in these experimental animals, the mechanism by which photoaddition of 8-methoxypsoralen (8MOP) to cellular constituents increases the immunogenicity of target T cells has not yet been fully elucidated. 12 Additional insight into the therapeutic response to photopheresis is available through the long-term follow-up of the initial study patients. We update the status of the 29 erythrodermic patients in the initial study and report the effects of therapy from the standpoint of impact on the disease, toxicity, and the nature of the therapeutic response. TREATMENT
As described previously, 8 patients were treated on two consecutive days at approximately 4-week intervals. In short, 2 hours after ingestion of 8-MOP (0.6 mg/kg), leukapheresis was performed and leukocytes were additionally diluted with plasma and saline to yield a leukocyte-enriched fraction with a hematocrit of 3% to 7% in the presence of 50 to 200
427
Journal of the American Academy of Dermatology
428 Heald et al.
1.1 0)
1.0
c 0.9 "::;: .::;: ::J 0.8 ~
(f)
c 0
0.7
'f:: 0.6 0 a. 0
l0-
a...
0.5 0.4 0.3
0
12
24
36 48 Months
60
72
84
Fig. 1. Survival rate as function of time in 29 erythrodermic patients treated with photopheresis. X-axis is months of survival from time of diagnosis. Median survival was 60.33 months. ng/ml8- MOP. This mixture was then irradiated by pumping the cells through a 1 mm thick UVA transparent plate sitting between two banks of UVA-emitting bulbs that delivered 1 to 2 joules/ cm2 of UVA to the treated leukocytes. After exposure of the cells to UV energy, the treated blood was reinfused so that there was no net blood withdrawal. In those patients achieving a complete response, there was a gradual tapering of therapy. The complete response was initially maintained for 6 months of monthly treatments. At that point, 1 week per cycle was added every three cycles of therapy. Ifthe complete response was maintained, this progression was continued until the patient achieved an 8-week interval. After three cycles of therapy at this interval, without recurrence, therapy was discontinued. Any recurrence during the tapering process would necessitate a return to a monthly regimen. Patients achieving a partial response were continued on treatment cycles every 4 weeks. PATIENT FOLLOW-UP
Of 29 erythrodermic patients in the initial study, six patients achieved complete remission. Another six patients had more than 50% improvement ofskin scores (described previously in Edelson et a!.), 8 and five patients had either no change or deterioration of skin status. The remaining patients had an improvement in skin score associated with a variable improvement in the quality of life. The study patients
have continued to be followed up periodically at the participating centers. Skin scores, blood cell counts, and clinical data continue to be recorded on an annual basis. Adverse reaction forms were completed for intercurrent problems to be reported to the Food and Drug Administration and the participating investigators. LONG-TERM SURVIVAL
The 29 erythrodermic patients were reviewed and survival determined as a function ofduration oftime from diagnosis and time from initiation of photopheresis. Survival statistics were calculated by the actuarial or life-table method. Two patients were lost to follow-up. As shown in Fig. 1, the median survival of erythrodermic patients is 60.33 months from the time of diagnosis of the erythrodermic state. From the time that photopheresis was initiated, the median survival was 47.9 months. The survival of erythrodermic CTCL patients was examined in relation to their subgrouping by clinical response. Four of six complete responders maintained complete remissions. Complete remissions continue to be maintained in four patients with durations that continue to grow from their current lengths of 5, 6 (two patients), and 7 years of disease-free survival. One patient discontinued therapy after 13 cycles of therapy and was in remission for an additional 5 months before he relapsed with large cell lymphoma that involved the bone marrow
Volume 27 Number 3 September 1992
Photopheresis to treat erythrodermic CTCL 429
Fig. 2. A, Skin biopsy specimen from responding patient before photopheresis therapy. B, Same area after clinical response to photopheresis. Follow-up biopsy specimen shows scattered cells in the perivascular area but loss of epidermal and high dermal infiltrate.
and lymph nodes. In a second patient immunoblastic lymphoma developed with nodal effacement and cutaneous tumors. The nodal and tumor stage of these two patients did not respond to additional therapy. Five patients had no response to therapy. Of these patients, one elected to continue photopheresis and is still alive. The other four nonresponders died. Therapy was continued for the remaining 18 patients with intermediate responses. Nine of these patients continuemaintenancetherapy with monthly photopheresis.
perivascular and high dermal infiltrates of abnormal cells. As the infiltrates were reduced in response to therapy, the epidermal and high dermal cell collections decreased. Once the clinically evident erythroderma had resolved, follow-up biopsy specimens revealed abnormal cells in perivascular regions (Figs. 2 and 3). With continued therapy, which was then gradually tapered, and continued follow-up, no recurrence or evidence of CTCL was demonstrated in these complete responders. In three of these patients, the infiltrates completely resolved.
HISTOLOGY OF THE THERAPEUTIC RESPONSE
PREDICTORS OF A THERAPEUTIC RESPONSE
Three of the six complete responders underwent serial biopsies in the same anatomic areas during therapy with photopheresis. Pretreatment biopsy specimens uniformly showed epidermotropism with
To determine the peripheral blood T-cell capacity to respond to mitogens and T-cell subset distribution, at entry to the clinical trial patients underwent phytohemagglutinin A (PHA) lymphocyte
430 Heald et al.
Journal of the American Academy of Dermatology
Fig. 3. A, Skin biopsy specimen from responding patient before photopheresis therapy. B, Same area after clinical response to photopheresis. Follow-up biopsy specimen shows scattered cells in the perivascular area but loss of epidermal and high dermal infiltrate.
stimulation tests and flow cytometry with a battery of monoclonal antibodies. These laboratory findings were compared between responding groups and nonresponders. For statistical analysis, Student's t test was used for differences between the groups. A value of p less than 0.05 was considered significant. Twelve patients had more than 50% clearing of the skin, six of whom had complete response and five were nonresponders. As shown in Fig. 4, the PHA tests that were done at several of the participating institutions demonstrate no distinctive difference between these two groups. The mean stimulation index for the complete responders was 72 and for nonresponders was 42. This was not a significant difference (p > 0.05). The initial CD4jCD8 peripheral blood lymphocyte ratios, as shown in Fig. 5, show a mean of 2.2 for the patients later showing
more than 50% response whereas the nonresponders had a mean of 5.78. This difference was significant at p < 0.05. Another feature that was compared in the two groups of responses was the duration between diagnosis of erythrodermic CTCL and starting therapy. The group with a more than 50% response (as shown in Fig. 6) had a mean value of 11.8 months for this interval, whereas nonresponders had a mean of 27.6 months (p > 0.05). One of the most significant findings was the paucity of side effects caused by therapy. In none of the original study patients was therapy halted as a result of photopheresis effects. White blood cell counts were not suppressed below normal limits, and other blood elements such as platelets and erythrocytes were maintained at normal levels.
Volume 27 Number 3 September 1992
Photopheresis to treat erythrodermic CTCL 431 200
r----------------------..., o
150
100
o
o
o 50
o
o
0 ' - - - - - - - - - - ' - - - - - - - - -~" " - - - - - - - - '
CR
NR
Fig. 4. Stimulation index as calculated by the formula (CPM in stimulated cells - CPM controlsjCPM controls). Complete responders (CR) are at left and nonresponders (NR) at right. Mean stimulation index for the complete responders was 72 and for nonresponders 42. Difference was not significant (p > 0.05). 10,.-----------------------, o
8
o o
6
4
2
o o
o
13
o
o
O'---------'--------L.-----------'
CR
NR
Fig. 5. CD4/CD8 ratios in peripheral blood lymphocytes before starting photopheresis therapy. Those of complete responders (CR) are at left (mean 2.2) and nonresponders (NR) at right (mean 5.78). This difference was significant (p < 0.05).
DISCUSSION
CTCL is a malignancy of CD4+ helper/inducer T cells, which first appears with skin infiltration. I, 13 Its incidence has not been clearly established, but it has been suggested that it has a frequency at least equal to that of Hodgkin's disease. 14, 15 Once microscopically disseminated, CTCL often transforms to a fatal progressive phase characterized by dedifferentiation. 16 Whereas visceral tumors and lymph
node involvement are indicative of particularly poor prognosis, the extent and type of skin lesions were found to be the most accurate predictor of median survival time. 2-4 For that reason, the observation that photopheresis substantially decreased the se· verity of skin involvement in patients with erythrodermic CTCL8, 17 was encouraging and suggested that survival of these patients might be prolonged. In contrast to previous reports that conventional ther-
Journal of the American Academy of Dermatology
432 Heald et al. 60,.....----------------------, o
40 o
30
o
o
o
o
20 10
o o
o 0'---------'---------'----------'
B
CR
NR
Fig. 6. Duration in months between making diagnosis of CTCL and initiation of photo-
pheresis therapy. Complete responders (CR) are at left (mean 11.8 months) and nomesponders (NR) at right (mean 27.6 months). This difference was not significant (p > 0.05). apy does not improve survival of CTCL patients, 7 our findings indicate that photopheresis has increased the longevity of erythrodermic CTCL patients, including those with histologic evidence of lymph node involvement. The life-table method for analyzing survival is preferable in that it makes possible the use of all information accumulated to date. Patients observed for only 2, 3, or 4 years before the closing date of the study can still contribute useful information to the evaluation of 5-year survival. Because only 2 of the 29 erythrodermic patients were lost to follow-up, this is not a legitimate concern. The use ofpreviously published studies as controls is complicated by having different populations as the study groups. However, these studies provide the best estimates available. The largest series comparable to that reported here is 42 patients with "generalized erythema" in CTCL. 2,4 In this group there was a median survival of 30 months. The median survival of the 29 photopheresis-treated erythrodermic patients of 60.3 months compares favorably with the results of these previous studies. The historical control series was also a multicenter collection, as was the photopheresis study series. One report that reviewed tumor registry data noted that S6zary syndrome (not defined) had a median survival of 2.6 years from diagnosis. 5 The potential significance of our results should be underscored by our having included patients who had failed at least one conventional modality, possibly biasing our patient selection to those with an even poorer prognosis.
There is one constant difference in the two historical control studies and the photopheresis patient series. Each was collected at a different time. However, even the temporal difference between the historical control groups did not markedly alter their estimates (mean survivals within a month of each other). In addition, another survey has shown that there does not appear to be any improvement of CTCL patient survival in recently reported cases as opposed to those previously reported. 7 The relevance to prognosis of extent of initial response to photopheresis is emphasized by a comparison between patients who experienced clinical remissions and those with no response. Four of six complete responders remain alive and in continued remission, whereas only one of five nonresponders has survived. The maintenance of these remissions is strongly suggestive of a potent host immunologic response to the CTCL cells for two major reasons. Although only a small fraction ofthe body's burden of malignant cells was exposed to photoactivated drug and returned to the patient, the remainder of the recognizable malignant cell pool diminished remarkably in size. In addition, it now appears that the usual natural progression ofthis phase of CTCL was interrupted. Studies in experimental animals support an immunologic basis for this response. Intravenous infusion of effector T cells pretreated with UVAactivated 8-MOP into immunologically naive recipient mice led to a strain-specific enhancement of allogeneic skin graft survival. 9 Similarly, intrave-
Volume 27 Number 3 September 1992
nous infusion oflymphocytes from adult MRL mice with a lupus erythematosus-like syndrome accompanied by high titers of anti-native DNA antibodies into young MRL mice prevented elevations of these antibody titers and slowed progression of the disease. 10 The mechanism by which exposure to photoactivated 8-MOP increases immunogenicity of effector T cells is not clear. However, it is noteworthy that in a preliminary study with antigen-specific murine cloned T cells,11 the impact appeared to be at the T-cell membrane and was clone specific, which suggests a role for a cell surface idiotype. Clinical studies have shown disease-modifying effects of photopheresis on patients with rheumatoid arthritis,18 pemphigus vulgaris,19 AIDS-related complex,2o and scleroderma. 21 The mechanism of the therapeutic similarities of these conditions will need further study. Itis apparent in previous reports and in this article that the toxicity of photopheresis is minimal. Whereas a minority of patients undergoing photopheresis experienced transiently increased erythroderma after reinfusion of the treated leukocytes, those sequelae frequently associated with systemic chemotherapy, such as bone marrow suppression, hair loss, and gastrointestinal erosions, were not encountered. It seems likely that the immunologic integrity of the patient will be a determinant in the response to photopheresis. This suggestion is supported by the clinical response, which was greatest in patients with more normal CD4jCD8 ratios. As the disease progresses, the patients become less immunocompetent similar to patients with progressive chronic lymphocytic leukemia. Another factor that contributes to the death of the patient is the evolution of subclones with either decreased surface antigenicity or rapid growth patterns, either of which could lead to failure of the treatment. This is presumably what happened to the two patients who had relapses after a complete response. Future studies should focus on trying to enhance the immunologic integrity of the patient and in arresting the evolution of subclones. Efforts to combine photopheresis with other modalities, such as with electron beam radiotherapy in patients with tumor stage CTCL or with interferon in partially responsive patients with erythrodermic CTCL, are under way. REFERENCES 1. Broder S, Edelson RL, Lutzner MA, et al. The Sezary syndrome: a malignant proliferation of helper T cells. J Clin Invest 1976;58:1297-306.
Photopheresis to treat erythrodermic CTCL 433 2. Lamberg SI, Green SB, Byar DP, et al. Status report of376 mycosis fungoides patients at 4 years: Mycosis Fungoides Cooperative Group. Cancer Treat Rep 1979;63:701-11. 3. Lamberg SI, Green SB, Byar DP, et al. Clinical staging for cutaneous T-celllyrnphoma. Ann Intern Med 1984;100: 187-92. 4. Green SB, Byar DP, Lamberg SI. Prognostic variables in mycosis fungoides. Cancer 1981;47:2671-7. 5. Weinstock MA, Horm JW. Population-based estimate of survival and determinants of prognosis with mycosis fungoides. Cancer 1988;62:1658-61. 6. Kaye FJ, Bunn PA, SteinbergSM, et al. Arandomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med 1989;321:1784-90. 7. Weinstock MA, Horm JW. Mycosis Fungoides in the United States: increasing incidence and descriptive epidemiology. JAMA 1988;260:42-6. 8. Edelson RL, Berger CL, Gasparro FP, et al. Treatment of cutaneous T-celllyrnphoma byextracorporealphotochemotherapy. N Engl J Med 1987;316:297-303. 9. Perez MI, Edelson RL, LaRoche L, et al. Inhibition of anti-skin allograft immunity by infusions with syngeneic photoinactivated effector lymphocytes. J Invest Dermatol 1989;92:669-74. 10. Berger CL, Perez M, Laroche L, et al. Inhibition of autoimmune disease in a murine model of systemic lupus erythematosus induced by exposure to syngeneic photoinactivated lymphocytes. J Invest DermatoI1990;94:52-7. 11. Pepino P, Berger CL, Fuzesi L, et al. Primate cardiac alloand xenotransplantation: modulation of the immune response with photochemotherapy. Eur Surg Res 1989;21: 105-13. 12. Gasparro FP, Dell'Amico R, Goldminz D, et al. Molecular aspects of extracorporeal photochemotherapy. Yale J BioI Med 1989;62:579-93. 13. Edelson R. Membrane properties of the abnormal cells of cutaneous T-cell lymphoma. Ann Intern Moo 1975;83:53642. 14. Edelson R. Cutaneous T celllyrnphoma: mycosis fungoides, Sezary syndrome, and other variants. JAM ACAD DERMA. TOL 1980;2:89-106. 15. Epstein WL, Bystryn J-C, Edelson RL, et al. Nonmelanoma skin cancer, melanomas, warts, and viral oncogenesis. JAM ACAD DERMATOL 1984;11:960-70. 16. Salhany KE, Cousar JB, Greer JP, et al. Transformation of cutaneous T-celilyrnphoma to large cell lymphoma. Am J PathoI1988;132:265-73. 17. Heald P, Perez M, Christensen I, et al. Treatment of cutaneous T-celllyrnphoma: the Yale-New Haven Hospital experience. Yale J Bioi Med 1990;62:629-38. 18. Malawista S, Trock D, Edelson R. The treatment of rheumatoid arthritis by extracorporea1 photochemotherapy. Arthritis Rheum 1991;34:646-54. 19. Rook A, Jegasothy B, Heald P, et aI. Extracorporeal photochemotherapy for drug-resistant pemphigus. Ann Intern Moo 1990;112:303-5. 20. Bisaccia E, Berger C, Klainer AS. Extracorporeal photopheresis in the treatment of AIDS-related complex: a pilot study. Ann Intern Med 1990;113:270-5. 21. Rook AH, Freundlich B, Jegasothy BV, et al. Treatment of systemic sclerosis with extracorporeal photochemotherapy: results of a multicenter trial. Arch Dermatol1992; 128:33746.
Cutaneous T -cell lymphoma (CTCL) is a malignancy of rnature T cells of the helper phenotype that initially invade the skin. I Clinical evolution of CTCL to widespread skin erythroderma, overt lymph node infiltration, or skin tumor development is associated with a poor prognosis. 2-6 A tumor registry survey suggested that the overall outcome of CTCL may not be affected by therapeutic advances. 7 A recent randomized trial supported that suggestion by finding that the overall survival of CTCL was not altered by conventional radio/chemotherapy despite palliative effects. 6 Extracorporeal photochemotherapy (photopheresis) has been shown in a multicenter study to decrease skin involvement in the study group of 29 patients with erythrodermic CTCL. 8 The potential From the Departments of Dermatology, Yale University School of Medicine, New Havena ; University of Pennsylvania, Philadelphia b; University of California, San Franciscoc; University of Vienna, Austriad; University of Pittsburghe; and Columbia College of Physicians and Surgeons, New YorkJ Reprint requests; Peter Heald, MD, 500 LCI, 333 Cedar St., New Haven, CT 06510.
16(1/37438
significance of those findings was suggested by studies in rodents indicating that reinfusion of similarly treated pathogenic T cells produces disease-modifying immunologic effects. 9- 11 In clinical photopheresis or in these experimental animals, the mechanism by which photoaddition of 8-methoxypsoralen (8MOP) to cellular constituents increases the immunogenicity of target T cells has not yet been fully elucidated. 12 Additional insight into the therapeutic response to photopheresis is available through the long-term follow-up of the initial study patients. We update the status of the 29 erythrodermic patients in the initial study and report the effects of therapy from the standpoint of impact on the disease, toxicity, and the nature of the therapeutic response. TREATMENT
As described previously, 8 patients were treated on two consecutive days at approximately 4-week intervals. In short, 2 hours after ingestion of 8-MOP (0.6 mg/kg), leukapheresis was performed and leukocytes were additionally diluted with plasma and saline to yield a leukocyte-enriched fraction with a hematocrit of 3% to 7% in the presence of 50 to 200
427
Journal of the American Academy of Dermatology
428 Heald et al.
1.1 0)
1.0
c 0.9 "::;: .::;: ::J 0.8 ~
(f)
c 0
0.7
'f:: 0.6 0 a. 0
l0-
a...
0.5 0.4 0.3
0
12
24
36 48 Months
60
72
84
Fig. 1. Survival rate as function of time in 29 erythrodermic patients treated with photopheresis. X-axis is months of survival from time of diagnosis. Median survival was 60.33 months. ng/ml8- MOP. This mixture was then irradiated by pumping the cells through a 1 mm thick UVA transparent plate sitting between two banks of UVA-emitting bulbs that delivered 1 to 2 joules/ cm2 of UVA to the treated leukocytes. After exposure of the cells to UV energy, the treated blood was reinfused so that there was no net blood withdrawal. In those patients achieving a complete response, there was a gradual tapering of therapy. The complete response was initially maintained for 6 months of monthly treatments. At that point, 1 week per cycle was added every three cycles of therapy. Ifthe complete response was maintained, this progression was continued until the patient achieved an 8-week interval. After three cycles of therapy at this interval, without recurrence, therapy was discontinued. Any recurrence during the tapering process would necessitate a return to a monthly regimen. Patients achieving a partial response were continued on treatment cycles every 4 weeks. PATIENT FOLLOW-UP
Of 29 erythrodermic patients in the initial study, six patients achieved complete remission. Another six patients had more than 50% improvement ofskin scores (described previously in Edelson et a!.), 8 and five patients had either no change or deterioration of skin status. The remaining patients had an improvement in skin score associated with a variable improvement in the quality of life. The study patients
have continued to be followed up periodically at the participating centers. Skin scores, blood cell counts, and clinical data continue to be recorded on an annual basis. Adverse reaction forms were completed for intercurrent problems to be reported to the Food and Drug Administration and the participating investigators. LONG-TERM SURVIVAL
The 29 erythrodermic patients were reviewed and survival determined as a function ofduration oftime from diagnosis and time from initiation of photopheresis. Survival statistics were calculated by the actuarial or life-table method. Two patients were lost to follow-up. As shown in Fig. 1, the median survival of erythrodermic patients is 60.33 months from the time of diagnosis of the erythrodermic state. From the time that photopheresis was initiated, the median survival was 47.9 months. The survival of erythrodermic CTCL patients was examined in relation to their subgrouping by clinical response. Four of six complete responders maintained complete remissions. Complete remissions continue to be maintained in four patients with durations that continue to grow from their current lengths of 5, 6 (two patients), and 7 years of disease-free survival. One patient discontinued therapy after 13 cycles of therapy and was in remission for an additional 5 months before he relapsed with large cell lymphoma that involved the bone marrow
Volume 27 Number 3 September 1992
Photopheresis to treat erythrodermic CTCL 429
Fig. 2. A, Skin biopsy specimen from responding patient before photopheresis therapy. B, Same area after clinical response to photopheresis. Follow-up biopsy specimen shows scattered cells in the perivascular area but loss of epidermal and high dermal infiltrate.
and lymph nodes. In a second patient immunoblastic lymphoma developed with nodal effacement and cutaneous tumors. The nodal and tumor stage of these two patients did not respond to additional therapy. Five patients had no response to therapy. Of these patients, one elected to continue photopheresis and is still alive. The other four nonresponders died. Therapy was continued for the remaining 18 patients with intermediate responses. Nine of these patients continuemaintenancetherapy with monthly photopheresis.
perivascular and high dermal infiltrates of abnormal cells. As the infiltrates were reduced in response to therapy, the epidermal and high dermal cell collections decreased. Once the clinically evident erythroderma had resolved, follow-up biopsy specimens revealed abnormal cells in perivascular regions (Figs. 2 and 3). With continued therapy, which was then gradually tapered, and continued follow-up, no recurrence or evidence of CTCL was demonstrated in these complete responders. In three of these patients, the infiltrates completely resolved.
HISTOLOGY OF THE THERAPEUTIC RESPONSE
PREDICTORS OF A THERAPEUTIC RESPONSE
Three of the six complete responders underwent serial biopsies in the same anatomic areas during therapy with photopheresis. Pretreatment biopsy specimens uniformly showed epidermotropism with
To determine the peripheral blood T-cell capacity to respond to mitogens and T-cell subset distribution, at entry to the clinical trial patients underwent phytohemagglutinin A (PHA) lymphocyte
430 Heald et al.
Journal of the American Academy of Dermatology
Fig. 3. A, Skin biopsy specimen from responding patient before photopheresis therapy. B, Same area after clinical response to photopheresis. Follow-up biopsy specimen shows scattered cells in the perivascular area but loss of epidermal and high dermal infiltrate.
stimulation tests and flow cytometry with a battery of monoclonal antibodies. These laboratory findings were compared between responding groups and nonresponders. For statistical analysis, Student's t test was used for differences between the groups. A value of p less than 0.05 was considered significant. Twelve patients had more than 50% clearing of the skin, six of whom had complete response and five were nonresponders. As shown in Fig. 4, the PHA tests that were done at several of the participating institutions demonstrate no distinctive difference between these two groups. The mean stimulation index for the complete responders was 72 and for nonresponders was 42. This was not a significant difference (p > 0.05). The initial CD4jCD8 peripheral blood lymphocyte ratios, as shown in Fig. 5, show a mean of 2.2 for the patients later showing
more than 50% response whereas the nonresponders had a mean of 5.78. This difference was significant at p < 0.05. Another feature that was compared in the two groups of responses was the duration between diagnosis of erythrodermic CTCL and starting therapy. The group with a more than 50% response (as shown in Fig. 6) had a mean value of 11.8 months for this interval, whereas nonresponders had a mean of 27.6 months (p > 0.05). One of the most significant findings was the paucity of side effects caused by therapy. In none of the original study patients was therapy halted as a result of photopheresis effects. White blood cell counts were not suppressed below normal limits, and other blood elements such as platelets and erythrocytes were maintained at normal levels.
Volume 27 Number 3 September 1992
Photopheresis to treat erythrodermic CTCL 431 200
r----------------------..., o
150
100
o
o
o 50
o
o
0 ' - - - - - - - - - - ' - - - - - - - - -~" " - - - - - - - - '
CR
NR
Fig. 4. Stimulation index as calculated by the formula (CPM in stimulated cells - CPM controlsjCPM controls). Complete responders (CR) are at left and nonresponders (NR) at right. Mean stimulation index for the complete responders was 72 and for nonresponders 42. Difference was not significant (p > 0.05). 10,.-----------------------, o
8
o o
6
4
2
o o
o
13
o
o
O'---------'--------L.-----------'
CR
NR
Fig. 5. CD4/CD8 ratios in peripheral blood lymphocytes before starting photopheresis therapy. Those of complete responders (CR) are at left (mean 2.2) and nonresponders (NR) at right (mean 5.78). This difference was significant (p < 0.05).
DISCUSSION
CTCL is a malignancy of CD4+ helper/inducer T cells, which first appears with skin infiltration. I, 13 Its incidence has not been clearly established, but it has been suggested that it has a frequency at least equal to that of Hodgkin's disease. 14, 15 Once microscopically disseminated, CTCL often transforms to a fatal progressive phase characterized by dedifferentiation. 16 Whereas visceral tumors and lymph
node involvement are indicative of particularly poor prognosis, the extent and type of skin lesions were found to be the most accurate predictor of median survival time. 2-4 For that reason, the observation that photopheresis substantially decreased the se· verity of skin involvement in patients with erythrodermic CTCL8, 17 was encouraging and suggested that survival of these patients might be prolonged. In contrast to previous reports that conventional ther-
Journal of the American Academy of Dermatology
432 Heald et al. 60,.....----------------------, o
40 o
30
o
o
o
o
20 10
o o
o 0'---------'---------'----------'
B
CR
NR
Fig. 6. Duration in months between making diagnosis of CTCL and initiation of photo-
pheresis therapy. Complete responders (CR) are at left (mean 11.8 months) and nomesponders (NR) at right (mean 27.6 months). This difference was not significant (p > 0.05). apy does not improve survival of CTCL patients, 7 our findings indicate that photopheresis has increased the longevity of erythrodermic CTCL patients, including those with histologic evidence of lymph node involvement. The life-table method for analyzing survival is preferable in that it makes possible the use of all information accumulated to date. Patients observed for only 2, 3, or 4 years before the closing date of the study can still contribute useful information to the evaluation of 5-year survival. Because only 2 of the 29 erythrodermic patients were lost to follow-up, this is not a legitimate concern. The use ofpreviously published studies as controls is complicated by having different populations as the study groups. However, these studies provide the best estimates available. The largest series comparable to that reported here is 42 patients with "generalized erythema" in CTCL. 2,4 In this group there was a median survival of 30 months. The median survival of the 29 photopheresis-treated erythrodermic patients of 60.3 months compares favorably with the results of these previous studies. The historical control series was also a multicenter collection, as was the photopheresis study series. One report that reviewed tumor registry data noted that S6zary syndrome (not defined) had a median survival of 2.6 years from diagnosis. 5 The potential significance of our results should be underscored by our having included patients who had failed at least one conventional modality, possibly biasing our patient selection to those with an even poorer prognosis.
There is one constant difference in the two historical control studies and the photopheresis patient series. Each was collected at a different time. However, even the temporal difference between the historical control groups did not markedly alter their estimates (mean survivals within a month of each other). In addition, another survey has shown that there does not appear to be any improvement of CTCL patient survival in recently reported cases as opposed to those previously reported. 7 The relevance to prognosis of extent of initial response to photopheresis is emphasized by a comparison between patients who experienced clinical remissions and those with no response. Four of six complete responders remain alive and in continued remission, whereas only one of five nonresponders has survived. The maintenance of these remissions is strongly suggestive of a potent host immunologic response to the CTCL cells for two major reasons. Although only a small fraction ofthe body's burden of malignant cells was exposed to photoactivated drug and returned to the patient, the remainder of the recognizable malignant cell pool diminished remarkably in size. In addition, it now appears that the usual natural progression ofthis phase of CTCL was interrupted. Studies in experimental animals support an immunologic basis for this response. Intravenous infusion of effector T cells pretreated with UVAactivated 8-MOP into immunologically naive recipient mice led to a strain-specific enhancement of allogeneic skin graft survival. 9 Similarly, intrave-
Volume 27 Number 3 September 1992
nous infusion oflymphocytes from adult MRL mice with a lupus erythematosus-like syndrome accompanied by high titers of anti-native DNA antibodies into young MRL mice prevented elevations of these antibody titers and slowed progression of the disease. 10 The mechanism by which exposure to photoactivated 8-MOP increases immunogenicity of effector T cells is not clear. However, it is noteworthy that in a preliminary study with antigen-specific murine cloned T cells,11 the impact appeared to be at the T-cell membrane and was clone specific, which suggests a role for a cell surface idiotype. Clinical studies have shown disease-modifying effects of photopheresis on patients with rheumatoid arthritis,18 pemphigus vulgaris,19 AIDS-related complex,2o and scleroderma. 21 The mechanism of the therapeutic similarities of these conditions will need further study. Itis apparent in previous reports and in this article that the toxicity of photopheresis is minimal. Whereas a minority of patients undergoing photopheresis experienced transiently increased erythroderma after reinfusion of the treated leukocytes, those sequelae frequently associated with systemic chemotherapy, such as bone marrow suppression, hair loss, and gastrointestinal erosions, were not encountered. It seems likely that the immunologic integrity of the patient will be a determinant in the response to photopheresis. This suggestion is supported by the clinical response, which was greatest in patients with more normal CD4jCD8 ratios. As the disease progresses, the patients become less immunocompetent similar to patients with progressive chronic lymphocytic leukemia. Another factor that contributes to the death of the patient is the evolution of subclones with either decreased surface antigenicity or rapid growth patterns, either of which could lead to failure of the treatment. This is presumably what happened to the two patients who had relapses after a complete response. Future studies should focus on trying to enhance the immunologic integrity of the patient and in arresting the evolution of subclones. Efforts to combine photopheresis with other modalities, such as with electron beam radiotherapy in patients with tumor stage CTCL or with interferon in partially responsive patients with erythrodermic CTCL, are under way. REFERENCES 1. Broder S, Edelson RL, Lutzner MA, et al. The Sezary syndrome: a malignant proliferation of helper T cells. J Clin Invest 1976;58:1297-306.
Photopheresis to treat erythrodermic CTCL 433 2. Lamberg SI, Green SB, Byar DP, et al. Status report of376 mycosis fungoides patients at 4 years: Mycosis Fungoides Cooperative Group. Cancer Treat Rep 1979;63:701-11. 3. Lamberg SI, Green SB, Byar DP, et al. Clinical staging for cutaneous T-celllyrnphoma. Ann Intern Med 1984;100: 187-92. 4. Green SB, Byar DP, Lamberg SI. Prognostic variables in mycosis fungoides. Cancer 1981;47:2671-7. 5. Weinstock MA, Horm JW. Population-based estimate of survival and determinants of prognosis with mycosis fungoides. Cancer 1988;62:1658-61. 6. Kaye FJ, Bunn PA, SteinbergSM, et al. Arandomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med 1989;321:1784-90. 7. Weinstock MA, Horm JW. Mycosis Fungoides in the United States: increasing incidence and descriptive epidemiology. JAMA 1988;260:42-6. 8. Edelson RL, Berger CL, Gasparro FP, et al. Treatment of cutaneous T-celllyrnphoma byextracorporealphotochemotherapy. N Engl J Med 1987;316:297-303. 9. Perez MI, Edelson RL, LaRoche L, et al. Inhibition of anti-skin allograft immunity by infusions with syngeneic photoinactivated effector lymphocytes. J Invest Dermatol 1989;92:669-74. 10. Berger CL, Perez M, Laroche L, et al. Inhibition of autoimmune disease in a murine model of systemic lupus erythematosus induced by exposure to syngeneic photoinactivated lymphocytes. J Invest DermatoI1990;94:52-7. 11. Pepino P, Berger CL, Fuzesi L, et al. Primate cardiac alloand xenotransplantation: modulation of the immune response with photochemotherapy. Eur Surg Res 1989;21: 105-13. 12. Gasparro FP, Dell'Amico R, Goldminz D, et al. Molecular aspects of extracorporeal photochemotherapy. Yale J BioI Med 1989;62:579-93. 13. Edelson R. Membrane properties of the abnormal cells of cutaneous T-cell lymphoma. Ann Intern Moo 1975;83:53642. 14. Edelson R. Cutaneous T celllyrnphoma: mycosis fungoides, Sezary syndrome, and other variants. JAM ACAD DERMA. TOL 1980;2:89-106. 15. Epstein WL, Bystryn J-C, Edelson RL, et al. Nonmelanoma skin cancer, melanomas, warts, and viral oncogenesis. JAM ACAD DERMATOL 1984;11:960-70. 16. Salhany KE, Cousar JB, Greer JP, et al. Transformation of cutaneous T-celilyrnphoma to large cell lymphoma. Am J PathoI1988;132:265-73. 17. Heald P, Perez M, Christensen I, et al. Treatment of cutaneous T-celllyrnphoma: the Yale-New Haven Hospital experience. Yale J Bioi Med 1990;62:629-38. 18. Malawista S, Trock D, Edelson R. The treatment of rheumatoid arthritis by extracorporea1 photochemotherapy. Arthritis Rheum 1991;34:646-54. 19. Rook A, Jegasothy B, Heald P, et aI. Extracorporeal photochemotherapy for drug-resistant pemphigus. Ann Intern Moo 1990;112:303-5. 20. Bisaccia E, Berger C, Klainer AS. Extracorporeal photopheresis in the treatment of AIDS-related complex: a pilot study. Ann Intern Med 1990;113:270-5. 21. Rook AH, Freundlich B, Jegasothy BV, et al. Treatment of systemic sclerosis with extracorporeal photochemotherapy: results of a multicenter trial. Arch Dermatol1992; 128:33746.
