Mycosis fungoides is an indolent primary cutaneous T-cell lymphoma (CTCL) that usually progresses from localized skin lesions to systemic disease. Sézary syndrome is a distinct variant characterized by generalized
ABSTRACT: Mycosis fungoides is an indolent primary cutaneous T-cell lymphoma (CTCL) that usually progresses from localized skin lesions to systemic disease. Sézary syndrome is a distinct variant characterized by generalized erythroderma and circulating cerebriform cells in the peripheral blood. The malignant cell in both diseases is a mature T cell, usually with a CD4- positive, CD8-negative phenotype. Among the treatment modalities used in these diseases are skin-directed therapy, single-agent and combination systemic chemotherapy, and, more recently, bioimmunotherapy. Pentostatin (Nipent), a potent inhibitor of adenosine deaminase, has activity in a wide range of lymphoid malignancies. At The Royal Marsden Hospital, we treated 29 cutaneous T-cell lymphoma patients with pentostatin, including 16 with Sézary syndrome, 5 with mycosis fungoides, and 8 with other cutaneous T-cell lymphomas. The median age of patients was 61 years (range, 26 to 87 years), with a male-female ratio of 2.5:1. The majority (N = 20) had received prior therapy. Pentostatin was administered at a dose of 4 mg/m²/wk for 4 weeks, and injections were continued every 1 to 2 weeks until maximum response. The overall response rate was 35%. However, only patients with Sézary syndrome achieved a good response, demonstrating an overall response rate of 62% (three complete responses plus seven partial responses). The median disease-free interval for responders was 9 months (range, 3 to 84 months). There was no significant treatment-related toxicity. We conclude that pentostatin is an effective single-agent therapy for patients with Sézary syndrome but not for those with other cutaneous T-cell lymphomas. [ONCOLOGY 14(Suppl 2):37-40, 2000]
Mycosis fungoides is an indolent primary cutaneous T-cell lymphoma (CTCL), characterized by infiltration of the skin by mature T lymphocytes. The early plaque stage usually progresses over time, with tumors developing and the lymph nodes and visceral organs becoming involved. Transformation to high-grade lymphoma may also occur. Sézary syndrome is a distinct variant characterized by generalized erythroderma and circulating cerebriform cells in the peripheral blood. Unspecified peripheral T-cell lymphomas with isolated skin involvement are included among the CTCLs.
A precise diagnosis of CTCL can be difficult to make. The early stages of mycosis fungoides may be hard to differentiate histologically and clinically from a variety of benign and premalignant skin conditions. More advanced disease must be differentiated from B-cell non-Hodgkins lymphoma and myeloid malignancies involving the skin. The circulating cells in Sézary syndrome resemble other mature T-cell leukemias, such as adult T-cell leukemia/lymphoma and T-prolymphocytic leukemia, which may also present with skin involvement.
Diagnosis rests on the characteristic skin histology, peripheral blood morphology in Sézary syndrome, and immunologic markers. Establishing clonality using polymerase chain reaction to detect T-cell receptor rearrangement may help differentiate CTCL from benign conditions. Skin pathology is similar in mycosis fungoides and Sézary syndrome, and is characterized by a dermal infiltrate of atypical lymphoid cells that extend into the epidermis, where clusters of cells form Pautriers microabscesses. The circulating lymphoid cells in Sézary syndrome are hyperchromatic, with a high nuclear-to-cytoplasmic ratio and a characteristic convoluted or cerebriform nucleus.
The nuclear folds and indentations are seen more clearly with an electron microscope. There are small- (Lutzner) and large-cell variants of Sézary cells. The bone marrow is often not involved. Surface marker analysis has shown that the malignant cell in both mycosis fungoides and Sézary syndrome is a mature T cell (CD2-positive, CD3-positive, terminal deoxynucleotidyl transferase-negative). The majority of these cells have a CD4-positive phenotype, usually restricted to the memory T-helper subset (CD45RA-positive). The T-cell antigen CD7 is often negative and CD25 is sometimes expressed, making it difficult to distinguish mycosis fungoides and Sézary sydrome from adult T-cell leukemia/lymphoma.
A variety of treatment modalities have been used in mycosis fungoides/Sézary syndrome.[2-5] Initial choice of therapy depends on the extent of disease. Patients with early-stage mycosis fungoides have a good prognosis and commonly receive only skin-directed therapy (psoralen ultraviolet light, photophoresis, electron-beam irradiation). For patients with more advanced mycosis fungoides and for those with Sézary syndrome, the outlook is poorer; standard therapies, including single-agent and combination chemotherapy, have been palliative rather than curative.
Recent studies have focused on immunomodulation, with the aim of enhancing host antitumor responses with agents such as interferon (Intron-A, Roferon-A) and interleukin-2 (Proleukin). Conjugated and unconjugated monoclonal antibodies have also been used. Pentostatin (2´-deoxycoformycin [Nipent]), a potent inhibitor of adenosine deaminase, has activity in a wide range of lymphoid malignancies.[7-15]
Adenosine deaminase deficiency is known to be selectively toxic to lymphoid cells.  High levels of adenosine deaminase in T cells make T-lymphoproliferative disease an obvious target for pentostatin therapy. Other purine analogs, such as cladribine (2-chlorodeoxyadenosine [Leustatin]), fludarabine (Fludara), and gemcitabine (Gemzar), have also shown activity in CTCL.[17-22]
In a large study of T-cell malignancies, we examined the role of pentostatin in the treatment of 29 patients with CTCL: 16 with Sézary syndrome and 13 with other CTCLs, including five with mycosis fungoides. The median age of patients was 61 years (range, 26 to 87 years) and the male-female ratio, 2.5:1. The majority of patients (N = 20) had received prior therapy with a variety of topical and systemic agents (Table 1). All patients manifested skin involvement, more than half had lymphadenopathy (57%), and one-quarter (24%) had splenomegaly (Table 1). The median white blood cell count at presentation was 20 x 109/L. All patients also had a mature post-thymic phenotype, with cells from the majority being CD4-positive, CD8- negative, and CD25-negative.
Pentostatin was administered by intravenous bolus injection at a dose of 4 mg/m²/wk for 4 weeks and then every 2 weeks until optimal response. Three of the Sézary syndrome patients who achieved a partial response (PR) continued to receive maintenance injections every 2 weeks. Patients received prophylaxis with co-trimoxazole and also, in some cases, with fluconazole (Diflucan) and acyclovir (Zovirax).
The criteria for response were as follows: a complete response (CR) consisted of normalization of blood counts, regression of organomegaly and skin lesions, and no residual disease in the bone marrow; a PR consisted of a 50% reduction in these parameters. Responses (CRs and PRs) were required to be sustained for at least 3 months. The duration of response was measured from the time of onset of objective clinical response to the time of relapse or last follow-up. No response was defined as less than a 50% improvement or a response duration of less than 3 months.
The results of pentostatin treatment in these patients with CTCL are summarized in Table 2. The overall response rate (CR plus PR) was 35%. However, a good response was seen only in patients with Sézary syndrome. Those patients had an overall response rate of 62% (3 CRs and 7 PRs), compared with no responses in patients with other CTCLs (including mycosis fungoides).
Responses were durable, with a median disease-free interval of 9 months (range, 3 to 84 months). One complete responder, who presented with widespread systemic involvement (spleen, liver, lung, lymph nodes, and 14 x109/L Sézary cells) and who was resistant to CHOP (cyclophosphamide, doxorubicin, Oncovin, and prednisone) chemotherapy remained in unmaintained CR for 7 years (ie, the patient received no maintenance therapy; Figure 1). Another patient, who achieved a CR, received pentostatin as first-line treatment and had a disease-free interval of 3 years.
Partial responses, which included significant skin improvement, lasted from 3 to 12 months, and three patients who achieved PRs received pentostatin as maintenance therapy. Symptomatic benefit, short of a PR, was observed in three patients with other CTCLs. The five patients with mycosis fungoides showed no objective benefit.
Pentostatin was well tolerated, with no major toxicity at the doses administered. The most common adverse effect was mild to moderate nausea, which was generally controlled with antiemetics. Significant hematologic, renal, and hepatic toxicity was not observed.
Our results indicate that Sézary syndrome is the only CTCL to benefit from therapy with pentostatin, when administered either as first-line treatment or to previously treated patients. Among 145 patients with a variety of mature
T-cell malignancies, the highest responses to pentostatin were observed in patients with Sézary syndrome. This underscores the importance of making a precise diagnosis in order to facilitate selection of treatment. The responses in patients with Sézary syndrome were durable, with unmaintained remissions of up to 7 years.
Pentostatin achieves good control of both the blood and skin manifestations of Sézary syndrome and merits consideration as first-line therapy in this disease. However, in other CTCL conditions, our experience using pentostatin as a single agent was disappointing. Use of pentostatin in combination or sequentially with other cytotoxic drugs or biological response modifiers may be more effective.
Other studies using pentostatin as a single agent in CTCL have reported response rates of 35% to 50%.[14,23-25] When used in combination with intermittent interferon, a response rate of 41% was reported. A comparison of our results with other studies is complicated by the variety of ways in which researchers have subclassified this group of diseases and the fact that some studies do not distinguish Sézary syndrome from other CTCLs. However, it appears that some studies have also reported that the best responses were seen in patients with Sézary syndrome, as in our study.[24-26]
Most of the studies using other purine analogs to treat CTCL have produced less promising results. Response rates of less than 30% with cladribine (range, 13% to 47%)[17-20] and 19% with fludarabine have been reported. Furthermore, significant myelotoxicity has limited the effectiveness of these treatment regimens. A newer nucleoside analog, gemcitabine, showed promising results in a phase II study of 13 pretreated CTCL patients (5 with mycosis fungoides and 8 with peripheral T-cell lymphoma) with a response rate of 69% (1 CR and 8 PRs). Toxicity was minimal.
Single-agent pentostatin has produced a maximal response of 62% in patients with Sézary syndrome. Combination strategies need to be explored if this response rate is to be improved. However, because patients with CTCL are already immunosuppressed by the disease, additional toxicity must be carefully avoided.
1. Matutes E, Catovsky D: Mature T-cell leukemias and leukemia/lymphoma syndromes: Review of our experience in 175 cases. Leuk Lymphoma 4:81-91, 1991.
2. Kemme DJ, Bunn PA Jr: State of the art therapy of mycosis fungoides and Sézary syndrome. Oncology 6:31-42, 1992 (erratum in Oncology 6:41, 1992).
3. Demierre MF, Foss FM, Koh HK: Proceedings of the International Consensus Conference on Cutaneous T-Cell Lymphoma (CTCL) Treatment Recommendations, Boston, Massachusetts, Oct 1 and 2, 1994. J Am Acad Dermatol 36:460-466, 1997.
4. Diamandidou E, Cohen PR, Kurzrock R: Mycosis fungoides and Sézary syndrome. Blood 88:2385-2409, 1996.
5. Russell-Jones R, Spittle MF: Manage-
ment of cutaneous lymphoma. Baillieres Clin Haematol 9:743-767, 1996.
6. Rook AH, Yoo EK, Grossman DJ, et al: Use of biological response modifiers in the treatment of cutaneous T-cell lymphoma. Curr Opin Oncol 10:170-174, 1998.
7. Grever MR, Siaw MF, Jacob WF, et al: The biochemical and clinical consequences of 2´deoxycoformycin in refractory lymphoproliferative malignancy. Blood 57:406-417, 1981.
8. Grever MR, Leiby JM, Kraut EH, et al: Low-dose deoxycoformycin in lymphoid malignancy. J Clin Oncol 3:1196-1201, 1985.
9. Spiers AS, Moore D, Cassileth PA, et al: Remissions in hairy cell leukemia with pentostatin (2´deoxycoformycin). N Engl J Med 316:825-830, 1987.
10. ODwyer PJ, Wagner B, Leyland-Jones B, et al: 2´Deoxycoformycin (pentostatin) for lymphoid malignancies: Rational development of an active new drug. Ann Intern Med 108:733-743, 1988.
11. Dillman RO, Mick R, McIntyre OR: Pentostatin in chronic lymphocytic leukemia: A phase II trial of Cancer and Leukemia Group B. J Clin Oncol 7:433-438, 1989.
12. Dearden C, Catovsky D: Deoxycoformycin in the treatment of mature B-cell malignancies. Br J Cancer 62:4-5, 1990.
13. Ho AD, Thaler J, Willemze R, et al: Pentostatin (2´deoxycoformycin) for the treatment of lymphoid neoplasms. Cancer Treat Rev 17:213-215, 1990.
14. Mercieca J, Matutes E, Dearden C, et al: The role of pentostatin in the treatment of T-cell malignancies: Analysis of response rate in 145 patients according to disease subtype. J Clin Oncol 12:2588-2593, 1994.
15. Dearden CE, Matutes E, Hilditch B, et al: Long-term follow-up of patients with hairy cell leukaemia after treatment with pentostatin or cladribine. Br J Haematol 106:515-519, 1999.
16. Dissing J, Knudsen B: Adenosine deaminase deficiency and combined immunodeficiency syndrome. Lancet 2:1316, 1972.
17. Saven A, Carrera CJ, Carson DA, et al: 2-Chlorodeoxyadenosine: An active agent in the treatment of cutaneous T-cell lymphoma. Blood 80:587-592, 1992.
18. Saven A, Piro LD: The newer purine analogs: Significant therapeutic advance in the management of lymphoid malignancies. Cancer 72:3470-3483, 1993.
19. Kuzel TM, Hurria A, Samuelson E, et al: Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma. Blood 8:906-911, 1996.
20. Kong LR, Samuelson E, Rosen ST, et al: 2-Chlorodeoxyadenosine in cutaneous T-cell lymphoproliferative disorders. Leuk Lymphoma 26:89-97, 1997.
21. Van Hoff DD, Dahlberg S, Hartstock RJ, et al: Activity of fludarabine monophosphate in patients with advanced mycosis fungoides:
A Southwest Oncology Group study. J Natl Cancer Inst 82:1353-1355, 1990.
22. Zinzani PL, Magagnoli M, Bendandi M, et al: Therapy with gemcitabine in pretreated peripheral T-cell lymphoma patients. Ann Oncol 9:1351-1353, 1998.
23. Grever MR, Bisaccia E, Scarborough DA, et al: An investigation of 2´deoxycoformycin in the treatment of cutaneous T-cell lymphoma. Blood 61:279-282, 1983.
24. Cummings FJ, Kim K, Neiman RS, et al: Phase II trial of pentostatin in refractory lymphomas and cutaneous T-cell disease. J Clin Oncol 9:565-571, 1991.
25. Greiner D, Olsen EA, Petroni G: Pentostatin (2´deoxycoformycin) in the treatment of cutaneous T-cell lymphoma. J Am Acad Dermatol 36:950-955, 1997.
26. Foss FM, Ihde DC, Breneman DL, et al: Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sézary syndrome. J Clin Oncol 10:1907-1913, 1992.