Treatment of Cutaneous T Cell Lymphoma

The treatment of cutaneous T cell lymphoma (CTCL), which includes mycosis fungoides and Sezary syndrome, has been in a state of continual change over recent decades, as new therapies are constantly emerging in the search for more effective treatments for the disease. However, prognosis and survival of patients with CTCL remains dependent upon overall clinical stage (stage IA-IVB) at presentation, as well as response to therapy. Past therapies have been limited by toxicity or the lack of consistently durable responses, and few treatments have been shown to actually alter survival, especially in the late stages of disease. Even aggressive chemotherapy has not been shown to improve overall survival compared to conservative sequential therapy in advanced disease, and adds the risk of immunosuppressive complications. Over the last decade, extracorporeal photopheresis has been the only single treatment that has been shown to improve survival in patients with Sezary syndrome, although its true efficacy and place in combination therapy remain unclear. Much of the focus of current research has been on combinations of skin-directed therapies and biological response modifiers, which improve response rates. The results of various trials over the years have also brought into favor the use of post-remission maintenance therapy with topical corticosteroids, topical mechlorethamine (nitrogen mustard), interferon-alpha, or phototherapy to prevent disease relapse. Recent novel developments in CTCL therapy include oral bexarotene, a retinoid X receptor-selective retinoid that has activity in all stages of CTCL, and the topical gel formulation of bexarotene, which plays a role in treating localized lesions. US Food and Drug Administration (FDA)-approved, oral systemic bexarotene has the advantage of a 48% overall response rate at a dosage of 300 mg/m(2)/day, and avoids immunosuppression and risk of central line and catheter-related infectious complications that are associated with other systemic therapies. Monitoring of triglycerides and use of concomitant lipid-lowering agents and thyroid replacement is required in most patients. Also recently FDA-approved, denileukin diftitox is the first of a novel class of fusion toxin proteins and is selective for interleukin-2R (CD25+) T cells, targeting the malignant T cell clones in CTCL. Denileukin diftitox is associated with capillary leak syndrome in 20 to 30% of patients, which may be ameliorated by hydration and corticosteroids. Higher response rates are possible by combining bexarotene with "statin" drugs and active CTCL therapies. Studies are being conducted on combining bexarotene and denileukin diftitox with other modalities. Biological response modifier therapies that are in current or future investigational trials include topical tazarotene, pegylated interferon, interleukin-2, and interleukin-12. At the forefront of systemic chemotherapy development, pegylated liposomal doxorubicin, gemcitabine, and pentostatin appear to have the greatest potential for success in CTCL therapy. Bone marrow transplantation, which is currently limited by the risk of graft-versus-host disease, offers the greatest potential for disease cure. Further developments for CTCL may include more selective immunomodulatory agents, vaccines, and monoclonal antibodies.     

Gemcitabine and vinorelbine treatment in cutaneous T‐cell lymphoma in four patients

Treatment options for advanced stage cutaneous T‐cell lymphoma (CTCL) are limited by the their efficacy and side‐effects profile. Gemcitabine, a pyrimidine analogue, has been reported to be efficacious in CTCL. Most of the studies published used gemcitabine as a single agent in treating advanced CTCL. Our small case series demonstrated that a combination of gemcitabine and vinorelbine induced partial remission in all four patients with refractory or advanced CTCL, although the effects were not sustained for a long duration (2–6 months). Two patients had neutropenia and one had acute hepatitis, requiring discontinuation of treatment.     

Somatostatin receptor scintigraphy in primary cutaneous T‐ and B‐cell lymphomas

Background Monitoring and repeated staging is of substantial importance in many patients with primary cutaneous T‐cell lymphomas (CTCL). For primary cutaneous B‐cell lymphomas (CBCL), extensive initial staging is the mainstay for correct diagnosis. Aim To evaluate the value of somatostatin receptor scintigraphy using the radiolabeled somatostatin analog ¹¹¹In‐pentetreotide in comparison to conventional imaging methods for the staging of patients with primary CTCL and primary CBCL. Methods Twenty‐two patients (15 patients with histologically verified CTCL and 7 patients with histologically verified CBCL) were included. Stage of disease was established by physical examination, laboratory screening, skin inspection, palpation of superficial lymph nodes, sonography and computed tomography (CT) in patients with advanced clinical stage. Focally elevated tracer uptake of ¹¹¹In‐pentetreotide was compared to common imaging modalities, physical aspect and digital photographs of the respective skin lesions. Results Of the 15 patients with CTCL, only 4 (27%) showed positive scintigraphic results, but not in all sites of lymphomatous involvement. None of the five patients with mycosis fungoides in stage I, nor any of the four patients with Sézary syndrome, had a positive ¹¹¹In‐ pentetreotide scan. Of the seven patients with CBCL three positive scintigraphic results (43%) could be obtained: in two patients with a follicular center lymphoma and one patient with a diffuse large B‐cell lymphoma – leg type, but again not in all apparent sites of lymphoma. Conclusions Based on our results, we do not recommend the use of somatostatin receptor scintigraphy for routine staging of patients with CTCL and CBCL. As our series includes only 22 patients, and the number of patients with rarer variants of CTCL was rather small, it might be too premature to abandon SST‐R in the staging of patients with cutaneous lymphomas.     

Cutaneous T cell lymphoma: update on treatment

Background Cutaneous T-cell lymphoma (CTCL) is a myeloproliferative disease with pronounced epidermotropism. The major subtypes of CTCL are mycosis fungoides and Sézary syndrome. Survival is dependent on the histological subtype and clinical stage. Early CTCL has a normal life expectancy, therefore early disease recognition and stage adapted treatment might help to ensure a good prognosis. Methods This is a review of recent advances in CTCL treatment based on literature review. Results Skin targeted therapies are useful for patch and limited plaque disease with phototherapy as the cornerstone of such treatments. More advanced disease will benefit from systemic mono- or combined treatments including drug therapy, extracorporeal photopheresis, and radiotherapy. In practice combined treatments may reduce adverse events and improve response rates. For selected younger patients, stem cell transplantation seems a third-line option. Conclusions The therapeutic spectrum for CTCL has been advanced during the last years, providing the opportunity of tailored treatment for patients.     

Dohi memorial lecture. Cutaneous T cell lymphoma

Cutaneous T cell lymphoma (CTCL) is a generic classification of clonally-derived malignancies of phenotypic helper/inducer T cells with a propensity to infiltrate the skin, migrate into the epidermis, localize in T cell zones of lymphoid structures and spare the bone marrow. One clinical presentation has a tendency to evolve into another as subclones of progressively less mature and less epidermotropic neoplastic cells arise and overgrow the relatively more mature other subclones. In this manner, localized, scaling plaques of typical parapsoriasis develop into more infiltrated plaques of classical mycosis fungoides which are themselves predecessors of tumor or erythroderma stage CTCL. With loss of epidermotropism, systemic dissemination occurs: first microscopically with blood involvement and seeding of internal organs and finally with visceral tumor formation. The relationship between CTCL and adult T cell lymphoma/leukemia is unclear because of tremendous overlap in the clinical and immunologic findings and because a fraction of patients with classical CTCL have low titers of anti-HTLV-1 antibodies. It is important to distinguish the skin-limited and systemic phases of CTCL in order to select appropriate treatments. New diagnostic techniques which are quite helpful include immunotyping with monoclonal antibodies, karyotype analysis and T cell receptor studies. Photopheresis, a very promising new therapeutic approach for the management of patients with systemically disseminated disease, and a suggested pathogenetic scheme are discussed.     

Staging and management of cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) accounts for two-thirds of cases of primary cutaneous lymphoma. Most variants of CTCL are indolent lymphoma, the most common being mycosis fungoides. In addition, Sézary syndrome, the leukaemic variant, has an aggressive clinical course. Accurate diagnosis and staging is critical in determining the prognosis of those with CTCL. The tumour, node, metastasis and blood stage needs to be documented and used to determine an overall stage from IA to IVB. Management of patients should be carried out by a multidisciplinary team. A full clinical examination should be made at all visits. Thorough investigations are needed at diagnosis and should be repeated during disease progression to allow initial staging and restaging. Treatment of patients with early-stage disease (IA-IIB) should be limited to skin-directed therapy. More advanced or resistant disease may be treated with systemic therapies such as extracorporeal photopheresis, immunotherapy, monoclonal antibody therapy, novel retinoids or chemotherapy, and where possible, patients should be entered into clinical trials.     

Hematopoietic stem cell transplantation in advanced cutaneous T‐cell lymphoma

We retrospectively reviewed data pertaining to five patients with cutaneous T‐cell lymphoma (CTCL) who had received hematopoietic stem cell transplantation (HSCT) between 2004 and 2015 at Kurume University Hospital, along with their clinical data until March 2016. For patients with advanced CTCL eligible for HSCT, autologous HSCT was performed when they responded well to chemotherapy, and allogeneic HSCT was selected for patients with advanced mycosis fungoides (MF)/Sézary syndrome (SS) and CTCL other than MF/SS with poor chemosensitivity. Two patients (primary cutaneous anaplastic large cell lymphoma and primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T‐cell lymphoma) who responded well to chemotherapy received autologous HSCT: one patient was alive in partial remission and the other died due to therapy‐related acute myeloid leukemia without disease relapse. In the remaining three patients with MF or SS, allogeneic HSCT was performed. Although one patient with MF died due to disease progression, the remaining two patients were alive in complete remission. Although there were two deaths in this study, the outcomes were considered satisfactory.     

Second Primary Malignancies in CTCL Patients from 1992 to 2011: A SEER-Based,Population-Based Study Evaluating Time from CTCL Diagnosis,Age, Sex,Stage, and CD30+ Subtype

Background

Cutaneous T-cell lymphoma (CTCL) is a diverse group of extranodal non-Hodgkin lymphomas with malignant T lymphocytes localizing in the skin. CTCL can mainly be classified as mycosis fungoides, Sézary syndrome, or primary cutaneous CD30+ lymphoma. Patients with CTCL have an increased risk of developing second primary malignancies.

Objective

Our objective was to analyze the overall incidence of second primary malignancies in patients with CTCL by age, sex, stage, and the primary cutaneous CD30+ lymphoproliferative subtype of CTCL, as this group has usually been excluded from previous analyses.

Methods

We used the Surveillance, Epidemiology, and End Results (SEER) database to evaluate CTCL cases diagnosed between 1992 and 2011. We calculated the multiple primary standardized incidence ratio, comparing the observed incidence of second primary malignant neoplasms in the CTCL patient population versus the general population.

Results

CTCL is associated with an overall increased risk of cancers. This incidence is greatest within the first year of diagnosis. The risk of secondary Hodgkin disease is greatest in patients aged ≥60 years; the risk of secondary non-Hodgkin lymphoma is greatest in patients aged 20–39. Males demonstrated a significantly increased risk of developing Hodgkin lymphoma, while females showed a significantly increased risk of developing bronchopulmonary malignancy. Overall, secondary malignancy incidence was significantly elevated for stage I and IV CTCL. Patients with CD30+ CTCL had a significantly higher incidence of Hodgkin lymphoma, non-Hodgkin lymphoma, and urinary cancers than the general population.

Conclusion

Occult secondary malignancies, particularly lymphomas, should be considered in adult CTCL patients, including those with the CD30+ subtype.

     

Hematopoietic stem cell transplantation for cutaneous T‐cell lymphoma: Summary of 11 cases from two facilities in Japan and Brazil

Some patients with cutaneous T‐cell lymphoma (CTCL) show a miserable clinical course and the only option that can induce long‐term remission for advanced CTCL may be hematopoietic stem cell transplantation (HSCT). So far, studies on HSCT for CTCL patients have been limited. In this study, we summarized 11 cases with CTCL treated with HSCT, including nine cases in Japan and two cases in Brazil. The patients were five cases with mycosis fungoides (MF), two cases with Sézary syndrome (SS), three cases with anaplastic large cell lymphoma, and one case with primary cutaneous peripheral T‐cell lymphoma, not otherwise specified (PTL‐NOS). Currently, seven out of 11 cases are alive (at 13–108 months after transplantation) and four died at 15 days to 14 months after transplantation. When focusing on the eight patients who received allogeneic HSCT for MF/SS and PTL‐NOS, all four patients at 45 years old or under are alive at present. One case showed relapse in the skin. On the other hand, one out of the other four patients at over 45 years old survived. Engraftment failure was seen in one case and all the other three cases experienced relapse. Although this is only a case series with a small number, our study has suggested that we should be careful about age when treating patients with MF/SS by allogeneic HSCT.     

Cutaneous T cell lymphoma: update of treatment

The state-of-the art therapy of cutaneous T cell lymphoma (CTCL) is reviewed. Commonly used treatments for early-stage (patch/plaque) mycosis fungoides (MF) include topical corticosteroids, mechlorethamine, carmustine, ultraviolet light B and PUVA. Total skin electron beam (TSEB) therapy is indicated for widespread infiltrated plaque and tumor stage disease. Low-dose methotrexate is often useful for resistant patch/plaque MF and erythrodermic CTCL. Interferon alpha (IFN-alpha) is indicated for methotrexate failures and recurrent tumors following TSEB therapy. Photopheresis may be helpful for early-stage erythrodermic CTCL but is very costly. Retinoids may be of value for early and moderately advanced CTCL particularly in combination with other agents such as IFN-alpha and PUVA. Systemic disease usually requires combination chemotherapy such as that used for non-Hodgkin's lymphoma; however, responses are usually short lived.     

U.K. consensus statement on safe clinical prescribing of bexarotene for patients with cutaneous T‐cell lymphoma

Background Bexarotene is a synthetic retinoid from the subclass of retinoids called rexinoids which selectively activate retinoid X receptors. It has activity in cutaneous T‐cell lymphoma (CTCL) and has been approved by the European Medicines Agency since 1999 for treatment of the skin manifestations of advanced‐stage (IIB–IVB) CTCL in adult patients refractory to at least one systemic treatment. In vivo bexarotene produces primary hypothyroidism which may be managed with thyroxine replacement. It also affects lipid metabolism, typically resulting in raised triglycerides, which requires prophylactic lipid‐modification therapy. Effects on neutrophils, glucose and liver function may also occur. These side‐effects are dose dependent and may be controlled with corrective therapy or dose adjustments. Objectives To produce a U.K. statement outlining a bexarotene dosing schedule and monitoring protocol to enable bexarotene prescribers to deliver bexarotene safely for optimal effect. Methods Leaders from U.K. supraregional centres produced this consensus statement after a series of meetings and a review of the literature. Results The statement outlines a bexarotene dosing schedule and monitoring protocol. This gives instructions on monitoring and treating thyroid, lipid, liver, blood count, creatine kinase, glucose and amylase abnormalities. The statement also includes algorithms for a bexarotene protocol and lipid management, which may be used in the clinical setting. Conclusion Clinical prescribing of bexarotene for patients with CTCL requires careful monitoring to allow safe administration of bexarotene at the optimal dose.     

Bexarotene therapy for mycosis fungoides and Sézary syndrome

Background Bexarotene (Targretin^®) is a synthetic retinoid which is licensed for the treatment of advanced refractory cutaneous T‐cell lymphoma (CTCL). Objectives To summarize our experience with bexarotene for patients with CTCL with the aim of assessing efficacy and safety. Methods A retrospective study of 66 patients (44 male, 22 female) with mycosis fungoides (40 patients) or Sézary syndrome (26 patients) who were commenced on bexarotene prior to August 2007 was carried out. Nineteen patients had early‐stage (IB–IIA) refractory mycosis fungoides and 47 patients had advanced‐stage CTCL (IIB–IVB). Results Fifty‐two out of 66 (79%) patients completed over 1 month of therapy with an intention‐to‐treat response rate of 44% (29/66). Of the patients, six (9%) had a complete response, 23 (35%) had a partial response, 15 (23%) had stable disease and eight (12%) had progressive disease. Median time to maximal response was 3 months (1–9 months). Median response duration was 8 months (1 to > 48 months). Median time to progression was 9 months (3–44 months). Fourteen patients (21%) did not complete a month of bexarotene therapy. Adverse effects of the whole group included central hypothyroidism in 100% (all grade II and managed with thyroid replacement) and hyperlipidaemia in 100% (all managed with lipid‐lowering therapy ± dose reduction). Responses were seen in all stages and were higher in advanced stages: 26% (five of 19) with early‐stage and 51% (24/47) of advanced‐stage disease. Responses were seen in skin, blood and lymph nodes. Twenty‐eight out of 66 patients were treated with bexarotene monotherapy and the remainder were on one or more additional anti‐CTCL therapies. Conclusions Our data demonstrate that bexarotene is well tolerated in most patients and responses are seen in almost half of patients with all disease stages. However partial responses were not graded and would include any improvement seen in the skin, blood and lymph node.     

T‐cell receptor gene rearrangement analysis of sequential biopsies in cutaneous T‐cell lymphomas with the Biomed‐2 PCR reveals transient T‐cell clones in addition to the tumor clone

Detection of a dominant T‐cell clone by T‐cell receptor (TCR) gene rearrangement analysis is often essential for the diagnosis of cutaneous T‐cell lymphomas (CTCL). The occurrence of T‐cell clones in addition to the diagnostic T‐cell clone during the course of CTCL has been reported, but the data of these studies have been contradictory. We retrospectively evaluated the data of 114 lesional skin biopsies from 26 patients with Mycosis fungoides and two patients with primary cutaneous anaplastic large cell lymphoma, which were analysed with the standardized Biomed‐2 PCR for the TCRγ and TCRβ locus. A dominant T‐cell clone was repetitively detected in 93% (26/28) of patients. Additional T‐cell clones appeared temporarily in 39% (11/28) of patients. Correlation with the clinical data did not show an association of the presence of additional T‐cell clones with age, number of treatments, progression of disease or survival. Our findings demonstrate that a persistent T‐cell clone, most likely the disease causing tumor clone, is detectable in almost all CTCL patients. In addition, transiently appearing T‐cell clones frequently occur during the course of disease. The biological relevance of these additional clones has still to be determined. However, it is important to take the possibility of additional T‐cell clones into account for diagnostic analyses.     

Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients

BACKGROUND: Although a number of studies have documented the long-term survival of patients with cutaneous T-cell lymphoma (CTCL), none have provided data as to the relative survival of all 4 skin stages. OBJECTIVE: We document survival of CTCL patients by T stage relative to that of an age-, sex-, and race-matched population. METHODS: The survival of 489 patients with CTCL registered since 1957 was compared with that of a California control population. RESULTS: For stage T1 (< 10% skin involved) there was no significant difference between the observed and expected survivals. For the other 3 stages the observed survival was significantly inferior to that of the expected survival (P = .002). At 10 years the relative survivals were: T2 (10% or more skin involved) 67.4%, T3 (tumor stage) 39.2%, T4 (generalized erythroderma) 41.0%. T2 plaque stage patients had an inferior relative survival (P = .001), whereas T2 patch stage patients did not. Lymphadenopathy had an unfavorable impact on prognosis. There was a strong trend toward diagnosing CTCL at an earlier stage in more recent years. We estimate that from 15% to 20% of our patients died of CTCL or related complications. CONCLUSION: The relative survival of CTCL patients worsens with increasing skin stage, although stages T3 and T4 had closely similar survivals. The great majority of patients with CTCL do not die of their disease.     

High expression of Dicer reveals a negative prognostic influence in certain subtypes of primary cutaneous T cell lymphomas

Background

Aberrant expression of microRNAs (miRNAs) has been implicated in oncogenesis of various tumors and primary cutaneous T cell lymphomas. Dicer, a ribonuclease III-like enzyme is essential for miRNA processing.

Objective

We initiated a retrospective study to characterize the alterations in the expression profile of Dicer in patients with primary cutaneous T cell lymphomas (CTCL).

Methods

A total of 50 consecutive patients with primary CTCL were studied, with the majority having mycosis fungoides (n = 34). Five patients had primary cutaneous CD 30+ anaplastic large cell lymphoma, four patients each had lymphomatoid papulosis and primary cutaneous CD4-positive small/medium T-cell lymphoma, one primary cutaneous γδ T cell lymphoma, one Sézary syndrome and another subcutaneous panniculitis-like T cell lymphoma of αβ-phenotype. Immunohistochemistry was performed on paraffin sections using a commercially available antibody against Dicer. Intensity of expression was correlated with clinical parameters including disease specific survival (DSS) and time to progression (TTP).

Results

After a median follow-up of 74 months (range: 1-271), 12/50 patients (24%) have died. Univariate and multivariate analysis for disease-specific survival showed Dicer expression and stage as a negative predictive factor in the sole group of MF patients (n = 34) as well as in the heterogeneous group of patients (n = 50), but not gender, histological subtype, primary localization of disease, age and recurrence of lymphoma (p > 0.05).

Conclusion

Our data suggest Dicer expression as a possible molecular marker in patients with MF and apparently indicate that miRNA(s) might be of clinical relevance in CTCL.     

Exfracorporeal Photochemotherapy in the Treatment of Cutaneous T-Cell Lymphoma

The term cutaneous T-cell lymphoma (CTCL) encompasses the spectrum of diseases characterized by a monoclonal proliferation of malignant T lymphocytes predominantly of the mature T-helper cell type. These include mycosis fungoides, which is usually localized to the skin for many years, and the Sezary syndrome, the leukemic variant in which characteristic, bizarre lymphatic cells with deeply indented or cerebriform nuclei, the Sezary cells, infiltrate lymph glands and internal organs such as the spleen, liver, lungs, heart, and bone marrow. The condition is more common in men after their fourth decade. The treatment of CTCL varies depending on the stage of the disease. The skin of the patient is the primary index of effectiveness of therapy. Options range from topical steroids, topical nitrogen mustard, X-irradiation, electron beam irradiation, and 8-methoxypsoralen (8-MOP) combined with ultraviolet A photochemotherapy (PUVA), to leukapheresis and systemic chemotherapy. More recently, extracorporeal photochemotherapy (ECPC) has been introduced. The safety and efficacy of this modality is further investigated in six patients who fulfilled the criteria of diagnosis of CTCL. The problems encountered in objectively evaluating the clinical responses in the patients are outlined and improvements in the protocol to overcome these are suggested. The proposed mechanism of action is an immunostimulatory one and a procedure that is relatively free from side effects; it offers promise as a potential treatment for a difficult cancer.     

Treatment of cutaneous T-cell lymphoma with combined immunomodulatory therapy: a 14-year experience at a single institution

OBJECTIVE: To determine the efficacy of multimodality biologic response therapy for patients with cutaneous T-cell lymphoma (CTCL). DESIGN: Retrospective cohort study over a 14-year period. SETTING: Tertiary care university hospital. PATIENTS: A consecutive sample of patients was studied, all 47 of whom carried the clinical and laboratory diagnosis of CTCL: 68% of patients had stage III or IV disease, and 89% had circulating malignant T cells. INTERVENTIONS: All 47 patients received photopheresis for 6 or more cycles. Thirty-one patients received treatment with a combination of photopheresis and 1 or more systemic immunostimulatory agents, including interferon alfa, interferon gamma, sargramostim, or systemic retinoids for 3 or more months. MAIN OUTCOME MEASURES: Differences in pretreatment prognostic factors, response rates, and survival between patients receiving multimodality therapy and single-modality therapy or historical controls. RESULTS: A total of 79% of patients responded to therapy: 26% had complete remission, and 53% had a partial remission. Median survival from initiation of therapy was 74 months. Median survival for patients with stages III and IV and peripheral blood involvement was 55 months compared with 31 months for historical controls. Compared with the photopheresis monotherapy group, the patients receiving combination immunomodulatory therapy had a worse prognosis at the time of treatment initiation based on multiple prognostic factors. The positive response rates and median survival times were 84% and 74 months, respectively, compared with 75% and 66 months, respectively, for the combination immunomodulatory and photopheresis monotherapy groups (P =.47 for positive response rates and P =.51 for survival). CONCLUSIONS: Patients with advanced CTCL and multiple poor prognostic factors who receive treatment with combination immunomodulatory therapy experience higher clinical response rates and longer survival than historical controls. Although the group who received combination therapy had worse prognostic factors at baseline, they had better response rates and overall survival compared with those receiving photopheresis monotherapy.     

Restoration of peripheral blood T cell repertoire complexity during remission in advanced cutaneous T cell lymphoma

In advanced stages, cutaneous T cell lymphomas (CTCL) are associated with increased mortality from infections and also increased susceptibility to skin malignancies. In this study, we analyzed the complexity of the peripheral blood T cell repertoire with a sensitive b-variable (BV) complementarity-determining region 3 (CDR3) spectratyping analysis and flow cytometry in three-stage IV CTCL/Sezary syndrome patients who achieved complete clinical remission after therapy. The T cell repertoire of peripheral blood T cells before treatment was profoundly abnormal across multiple BV subfamilies. Following treatment, CDR3 spectratype patterns showed dramatic restoration of normal diversity and complexity. However, absolute CD4 counts across multiple BV families remained low for many months, even after identifiable circulating malignant T cell populations were eliminated. These data suggest that the diversity of the T cell repertoire can be recovered after successful treatment of even advanced CTCL.