Mycosis fungoides and the Sézary syndrome

PURPOSE OF REVIEW: Mycosis fungoides and the Sézary syndrome represent a heterogeneous group of good-to-intermediate-risk non-Hodgkin lymphomas that have recently been identified as distinct histopathologic and clinical entities by the World Health Organization and European Organization for Research on the Treatment of Cancer lymphoma classification systems. Significant progress has been made in identifying and categorizing patients based on clinical prognostic factors, but there is little information regarding the etiology, molecular biology, and molecular genetics of these diseases. This review outlines recent advances in clinical diagnosis and prognosis as well as novel therapeutic approaches. RECENT FINDINGS: A number of reports have further defined clinical prognostic subgroups among early-stage patients and those with circulating Sézary cells. The recent availability and demonstrated efficacy of the oral RXR retinoid, bexarotene, has altered the treatment paradigm of early-stage patients who would not otherwise be exposed to systemic therapies. Novel targeted agents and receptor-directed therapies, including the fusion toxin, denileukin diftitox, histone deacetylase inhibitors, and novel nucleoside analog therapies, have demonstrated promising activity and are undergoing further clinical evaluation. The evolution of immunotherapy has been augmented by studies demonstrating the efficacy of peptide-loaded dendritic cells as well as the use of photopheresis to generate an anti-idiotype cytotoxic T-cell response. SUMMARY: This review will enumerate the most recent findings with respect to clinical staging, prognosis, and treatment of patients with mycosis fungoides and the Sézary syndrome. Novel treatment options will be reviewed and treatment paradigms will be outlined.     

Mycosis fungoides and the Sézary syndrome.

Mycosis fungoides (MF) and the Sézary syndrome are a group of extranodal non-Hodgkin's lymphomas of T-cell origin with primary cutaneous involvement. The group distinguishes itself from other primary cutaneous T-cell lymphomas (CTCLs) by its unique clinical features and histopathology. In its early stages, it often resembles common benign dermatoses, and therefore, a definitive diagnosis can be delayed. The affected T cells are characterized by a predominant CD4+ phenotype with frequent loss of CD7 (pan-T-cell antigen) and often demonstrate T-cell receptor (TCR) rearrangement. The prognosis of patients with MF is highly dependent on the extent and type of skin involvement. The initial cutaneous presentation of MF can be patches, plaques, tumors, or erythroderma. Patients who present with limited patch/plaque disease have an outstanding prognosis with an overall long-term survival that is similar to the expected survival of a matched control population. It is exceedingly rare for patients who present with limited or generalized patch/plaque disease without peripheral lymphadenopathy to have extracutaneous involvement. Therefore, the staging evaluation differs for patients with MF versus patients with other non-Hodgkin's lymphomas and should be tailored to the clinical presentation. Patients who have tumorous or erythrodermic skin involvement have a less favorable prognosis, and patients who present with extracutaneous disease have a poor prognosis. There are multiple therapeutic options for patients with MF and the Sézary syndrome. Selection of a specific treatment plan is based primarily on the clinical stage of the disease. The primary therapy for patients with patch/plaque disease without extracutaneous involvement is a topical regimen, whereas chemotherapy or other aggressive systemic regimens are reserved for those with recalcitrant disease or extracutaneous involvement. There is no evidence that early aggressive systemic therapy is preferable to conservative therapy in the management of limited disease. There are newer combination topical and/or systemic regimens that result in an improved clinical response and possibly a prolonged response duration. For advanced disease, standard therapies are often palliative and successful clinical response is often very short-lived. Therefore, all patients with recalcitrant or extracutaneous disease should be considered for newer investigative therapies.     

A mouse model for the Sézary syndrome

Background

The Sézary syndrome is an aggressive leukemic form of cutaneous T cell lymphoma and there is no cure of this disease. Until now there is no true animal model for Sézary syndrome, by which new drugs against the disease could be tested.

Methods

Immune deficient CB-17 SCID beige mice were injected subcutaneously with HUT78 cells, a cell line, derived from a Sézary syndrome patient. Developing tumors were analyzed by immunohistochemistry.

Results

Injected HUT78 cells formed tumors at the site of injection. In contrast to the Sézary syndrome in man, no malignant cells were observed in the blood of tumor bearing CB-17 SCID beige mice. The tumors appeared 44-62 days after injection and tumor bearing mice survived further 25 - 62 days until they had to be euthanized according to the guidelines of the Swiss animal protection law, since the tumors had reached the maximal allowed size.

Conclusion

Although the mouse model does not exactly match the human disease, it will be suited for tests of new substances for the treatment of the Sézary syndrome. The formation of an isolated tumor on the skin has the advantage that the effect of a potential drug can be directly monitored without the use of invasive methods.

     

Additional Her 2/neu gene copies in patients with Sézary syndrome

BACKGROUND: Her 2/neu gene amplification has been reported in several types of cancer. Monoclonal antibodies against the Her 2/neu receptor are used as a treatment in e.g. metastatic breast cancer. AIM: The aim of this study was to determine the frequency of additional Her 2/neu gene copies in relations to the number of chromosome 17 centromeres of patients with Sézary syndrome. METHODS: Fluorescence in situ hybridization (FISH) with probes specific for the Her 2/neu gene locus and the centromere of chromosome 17 was performed on nuclei from peripheral blood cells of 9 patients with Sézary syndrome. For analysis of Her 2/neu protein expression immunostaining was performed. In addition, FISH was used to analyze distribution of typical lymphocytes on cryo-cut sections of affected skin of two patients. RESULTS: 7/9 cases showed additional Her 2/neu gene copies in relation to the number of chromosome 17 centromeres. 4/5 cases with additional Her 2/neu gene copies in which immunostaining was performed expressed Her 2/neu protein. On cryo-cut sections atypical lymphocytes with additional Her 2/neu gene copies were detected in the dermis as well as in the epidermis of affected skin. DISCUSSION: These data suggest that Her 2/neu might be involved in the pathogenesis of Sézary syndrome and that Her 2/neu might be a promising target for antitumor therapy in a subgroup of patients.     

Diagnostic and prognostic importance of T-cell receptor gene analysis in patients with Sézary syndrome.

BACKGROUND: Sézary syndrome (SS) is characterized by erythroderma, peripheral lymphadenopathy, and circulating Sézary cells and is clinically heterogeneous. METHODS: T-cell receptor (TCR) gene analysis was performed using DNA extracted from peripheral blood mononuclear cells from 74 patients, and the results were correlated with a variety of other diagnostic parameters and patient outcomes. RESULTS: Two groups were identified: 66 patients with clonal TCR gene rearrangement (clonal patients) detected with Southern blot analysis and/or polymerase chain reaction/single-strand conformational polymorphism analysis and 8 patients with no clonal rearrangement detected (nonclonal patients) using either technique. Clonal patients were compared with nonclonal patients. The following median blood parameters were significantly greater in the clonal group: total white cell count (13.7 10(9)/L vs. 9.6 10(9)/L), lymphocyte count (4.9 10(9)/L vs. 2.2 10(9)/L), absolute Sézary count (3.22 10(9)/L vs. 0.99 10(9)/L), CD4 count (3.17 10(9)/L vs. 1.36 10(9)/L), and CD4:CD8 ratio (15.86 vs. 3.21). An expanded population of T-cells of a specific TCR variable beta subset was detected in 7 of 36 clonal patients and in 1 of 4 nonclonal patients. Cytogenetic analysis of peripheral blood from 1 nonclonal patient and 6 clonal patients was normal. The median survival from the time of diagnosis was 45 months in the clonal group, and 40 of 49 deaths were cutaneous T-cell lymphoma (CTCL)-related, whereas 3 deaths in the nonclonal group were unrelated to CTCL (P < 0.01; log-rank test). Multivariate proportional hazards analysis showed that the absolute Sézary count and lymph node status were independent prognostic variables (P = 0.016 and P = 0.036, respectively). CONCLUSIONS: TCR gene analysis defines a distinct clinicopathologic group of patients with SS. Clonal patients have a poor prognosis and are likely to die from leukemia/lymphoma, whereas nonclonal patients may have a reactive, inflammatory T-cell disorder. The authors suggest that the definitive diagnostic criteria for patients with SS should include the presence of a clonal TCR gene rearrangement.     

Preferential replication of Sézary cells in the epidermis.

Skin biopsies from three patients with Sézary Syndrome have been labeled in vitro with H-3Thymidine. Labeled cells have been counted in semithin Epon embedded sections and characterized by electron microscopic autoradiography. The ratio of labeled Sézary cells to total lymphocytes was two to four times higher in the epidermis than in the dermis. It is concluded that Sézary cells replicate in the skin and that epidermal cells seem to possess new blastogenic properties in Sézary Syndrome.     

Novel and highly recurrent chromosomal alterations in Sézary syndrome

This study was designed to identify highly recurrent genetic alterations typical of Sézary syndrome (Sz), an aggressive cutaneous T-cell lymphoma/leukemia, possibly revealing pathogenetic mechanisms and novel therapeutic targets. High-resolution array-based comparative genomic hybridization was done on malignant T cells from 20 patients. Expression levels of selected biologically relevant genes residing within loci with frequent copy number alteration were measured using quantitative PCR. Combined binary ratio labeling-fluorescence in situ hybridization karyotyping was done on malignant cells from five patients. Minimal common regions with copy number alteration occurring in at least 35% of patients harbored 15 bona fide oncogenes and 3 tumor suppressor genes. Based on the function of the identified oncogenes and tumor suppressor genes, at least three molecular mechanisms are relevant in the pathogenesis of Sz. First, gain of cMYC and loss of cMYC antagonists (MXI1 and MNT) were observed in 75% and 40% to 55% of patients, respectively, which were frequently associated with deregulated gene expression. The presence of cMYC/MAX protein heterodimers in Sézary cells was confirmed using a proximity ligation assay. Second, a region containing TP53 and genome maintenance genes (RPA1/HIC1) was lost in the majority of patients. Third, the interleukin 2 (IL-2) pathway was affected by gain of STAT3/STAT5 and IL-2 (receptor) genes in 75% and 30%, respectively, and loss of TCF8 and DUSP5 in at least 45% of patients. In sum, the Sz genome is characterized by gross chromosomal instability with highly recurrent gains and losses. Prominent among deregulated genes are those encoding cMYC, cMYC-regulating proteins, mediators of MYC-induced apoptosis, and IL-2 signaling pathway components.     

EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome

Several reviews and guidelines on the management of mycosis fungoides and Sézary syndrome (MF/SS) have been published; however, treatment strategies for patients with MF/SS vary from institution to institution and no European consensus has yet been established. There are few phase III trials to support treatment decisions for MF/SS and treatment is often determined by institutional experience. In order to summarise the available evidence and review 'best practices' from each national group, the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force met in September 2004 to establish European guidelines for the treatment of MF/SS. This article reviews the treatment regimens selected for inclusion in the guidelines and summarises the clinical data for treatments appropriate for each stage of MF/SS. Guideline recommendations are presented according to the quality of supporting data, as defined by the Oxford Centre for Evidence-Based Medicine. Skin-directed therapies are the most appropriate option for early-stage MF/SS and most patients can look forward to a normal life expectancy. Patients with advanced disease should be encouraged to participate in clinical trials and maintenance of quality of life should be paramount.     

Regulatory T cells and immunodeficiency in mycosis fungoides and Sézary syndrome

Cutaneous T-cell lymphoma (CTCL) is the term for diseases characterized by primary accumulation of malignant T cells in the skin. Patients with the two predominant clinical forms of CTCL called mycosis fungoides (MF) and Sézary syndrome (SS) characteristically develop severe immunodeficiency during disease progression and consequently patients with advanced disease frequently die of infections and not from the tumor burden. For decades, it has been suspected that the malignant T cells actively drive the evolving immunodeficiency to avoid antitumor immunity, yet, the underlying mechanisms remain unclear. The identification of a subset of highly immunosuppressive regulatory T cells (Tregs) triggered a variety of studies investigating if MF and SS are malignant proliferations of Tregs but seemingly discordant findings have been reported. Here, we review the literature to clarify the role of Tregs in MF and SS and discuss the potential mechanisms driving the immunodeficiency.     

Subcutaneous alemtuzumab for Sézary Syndrome in the very elderly

Sézary Syndrome (SS) is an aggressive T-cell malignancy often presenting in advanced age and associated with poor prognosis. There is no standard therapy and because of co-morbidities, elderly patients are particularly challenging to treat. Alemtuzumab is an anti-CD52 monoclonal antibody that has activity in SS but is profoundly immunosuppressive, leading to great hesitation about its use in older patients. We treated five octogenarian patients with SS with subcutaneous (SQ) alemtuzumab, at relapse or as initial therapy, for 5–9 weeks. With the exception of transient grade 1–2 hematological toxicity and asymptomatic cytomegalovirus (CMV) (two patients) and Epstein-Barr virus (EBV) (one patient) reactivation, no other toxicities were observed. The clinical and hematological complete response (CR) rate was 100%. Three patients achieved durable responses (8+ to 17+ months). Alemtuzumab was safely administered and showed significant activity in very elderly SS patients.     

Total skin electron radiation for patients with erythrodermic cutaneous T-cell lymphoma (mycosis fungoides and the Sézary syndrome)

BACKGROUND: There is limited published evidence regarding the efficacy of total skin electron beam radiation for patients with the diffuse erythrodermic form of mycosis fungoides. METHODS: Forty-five patients with erythrodermic mycosis fungoides were managed at McMaster University in Hamilton, Ontario, Canada (n=34), and at Yale University (n=11) between 1970 and 1996. All received radiation without neoadjuvant, concomitant, or adjuvant therapies. The median age was 67 years (range, 42-84 years). The male-to-female ratio was 2.2. Fifteen received radiation for the treatment of newly diagnosed disease. There were 28 with Stage III (T4 N0-1 M0), 13 with Stage IVA (T4 N2-3 M0), and 4 with Stage IVB (T4 N0-3 M1) disease, and 21 had blood involvement. The median radiation dose was 32 gray (Gy) (range, 4.8-40 Gy). The median treatment time was 21 days (range, 3-125 days). A technically more intense method of radiation (32-40 Gy and 4-6 MeV electrons) was administered to 23 patients. RESULTS: All patients responded. The rate of complete cutaneous remission was 60%, with 26% remaining progression free at 5 years. Remission was associated with more intense radiation (P=0.014 in multivariate analysis with adjustment for blood and staging information). With the more intense radiation, 74% attained remission, with 36% remaining progression free at 5 years. For 8 patients with Stage III disease without blood involvement, all entered remission, with 69% remaining progression free at 5 years. Twenty of 30 deaths were related to mycosis fungoides. The median overall survival was 3.4 years, with a 10-year estimate of 28%. The median cause specific survival was 5 years, with a 10-year estimate of 43%. Both overall and cause specific survival were associated with an absence of blood involvement (both P<0.03 in multivariate analysis). Age was not a significant factor. Toxicities of radiation were acceptable when radiation was administered over 6-9 weeks at 5 fractions per week. CONCLUSIONS: Total skin radiation is an efficient monotherapy for patients with erythrodermic mycosis fungoides. With more intense radiation, the rate of cutaneous remission is 74%, and 27% remain progression free at 10 years. Radiation may be most efficacious in Stage III, with no blood involvement. When there is blood, lymph node, or visceral involvement, combined modality therapies should be explored.     

Outcome of allogeneic hematopoietic stem cell transplantation for mycosis fungoides and Sézary syndrome

Although allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to provide prolonged remission of relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS), its role has not been fully evaluated. Here, the outcomes of allogeneic HSCT for patients with MF/SS were retrospectively evaluated by using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Forty-eight patients were evaluable and enrolled in the analysis. Median age was 45.5 years. Eighteen patients (38%) received myeloablative conditioning, and 33 (69%) received HSCT from an alternative donor. Disease status was complete or partial response in 25% of the patients and relapsed or refractory in the others. At the time of analysis, 18 patients were alive, with a median follow-up of 31.0 months (range, 3.8-31.1). Three-year overall survival (OS) and progression-free survival (PFS) were 30% (95%CI, 16-45%) and 19% (95%CI, 9-31%), respectively. Disease progression was not observed later than 17 months after transplantation. Both disease status and performance status at transplant significantly affected OS and PFS. Although our findings suggest that allogeneic HSCT provides long-term PFS in patients with MF/SS, the timing of transplantation should be decided carefully based on the disease status and the patient's condition in order to improve the outcome.     

Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous t-cell lymphomas (CTCL) (Mycosis fungoides and Sézary syndrome)

BackgroundForodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL).Patients and methodsIn this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients.ResultsAll 144 patients had performance status 0–2. The median duration of CTCL from diagnosis was 53 months (5–516 months). The median number of pretreatments was 4 (range: 3–15). No complete remissions were observed. In the efficacy group of patients, 11% achieved partial remission and 50% had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96% of all treated patients reported one or more adverse events (AEs) and 33% reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10%) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure.ConclusionOral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses.     

Review of the treatment of mycosis fungoides and sézary syndrome: a stage-based approach

The NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin's Disease were recently revised to include recommendations for treating mycosis fungoides and Sézary syndrome. These uncommon lymphomas require a specialized evaluation and use a unique TNMB staging system. Unlike the other forms of non-Hodgkin's lymphomas, stage overwhelmingly determines prognosis and defines radically different treatment approaches. For patients with early-stage disease, initial treatment with skin-directed therapies is preferred, and many patients never require systemic therapy. For patients with refractory or advanced-stage disease, biologic therapies are often the first choices, whereas chemotherapies are reserved for later in the disease course. Many milder therapies may be repeated several times in the disease course, and maintenance and tapering strategies are common. This article also discusses the emerging role of allogeneic stem cell transplantation.     

Interferon and low dose methotrexate improve outcome in refractory mycosis fungoides/Sézary syndrome

Treatment of refractory mycosis fungoides and Sézary syndrome remain unsatisfactory. In this study, we assessed the efficacy and toxicity of low-dose methotrexate (10 mg/m(2), biweekly) and interferon (9.0 MU, three times a week) as induction therapy by 6 or 12 months, followed, if patients achieved a complete remission, by interferon maintenance until toxicity or relapse. In an intent-to-treat analysis, 158 patients were considered evaluable. Complete response (biopsy proven) was observed in 112 patients (49 [31%] at 6 months and 63 [49%] at 12 months); thus, the complete response rate was 74%. With a median follow-up of 155 months (range, 62-181), progression-free disease was 71% and overall survival was 69%. Acute toxicity was mild, treatment was well tolerated, and to date no late toxicity has been observed. We conclude that this regimen is a benefit to this setting of patients, with excellent outcome and mild toxicity.