Mogamulizumab induces long term immune restoration and reshapes tumoral heterogeneity in Sézary syndrome

Sezary syndrome (SS) is a leukemic form of cutaneous T-cell lymphoma and is chemo-resistant. Allogeneic hematopoietic stem cell transplantation is a promising therapy for SS; however, relapse is common. Therapeutic options after relapse have not been established. We managed an SS patient with hematological relapse within one month after transplantation. After discontinuation of immunosuppressants, she achieved complete remission and remained relapse-free. The chimeric analyses of Tcells showed that the full recipient type became complete donor chimera after immunological symptoms. This clinical course suggested that discontinuation of immunosuppressants may result in a graftversus- tumor effect, leading to the eradication of lymphoma cells.

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Long-term Cytapheresis in the Treatment of Sézary-syndrome

The International Journal of Artificial Organs ◽

10.1177/039139888400700309 ◽

1984 ◽

Vol 7 (3) ◽

pp. 143-146 ◽

Cited By ~ 1

Author(s):

N. Müller ◽

C.-E. Lange

Keyword(s):

Sézary Syndrome ◽

Sezary Syndrome

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Phase I/II Study of Oral FodosineTM, a PNP Inhibitor in Refractory Cutaneous T-Cell Lymphoma Patients.

Blood ◽

10.1182/blood.v106.11.2683.2683 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2683-2683 ◽

Cited By ~ 1

Author(s):

Madeleine Duvic ◽

Debra Breneman ◽

Maureen Cooper ◽

Gustavo Fonseca ◽

J. Claude Bennett ◽

...

Keyword(s):

T Cell ◽

Mycosis Fungoides ◽

Progressive Disease ◽

Treatment Cycle ◽

Cell Lymphoma ◽

Preliminary Evidence ◽

Sézary Syndrome ◽

Sezary Syndrome ◽

Minor Response

Abstract Suppression of T-cell immunity seen in children with inherited purine nucleoside phosphorylase (PNP) deficiency supports the potential application of PNP inhibitors for the therapy of T-cell malignancies. Forodesine (FodosineTM) is a specific PNP inhibitor that raises plasma 2′-deoxyguanosine (dGuo) and intracellular dGTP levels, leading to T-cell apoptosis. IV administration of forodesine has shown activity in cutaneous T-cell lymphoma (CTCL) patients. To determine the safety, pharmacokinetics and pharmacodynamics of oral forodesine in patients with refractory CTCL, as well as preliminary evidence of efficacy, five cohorts of patients (≥ 3patients per cohort) were evaluated sequentially, receiving forodesine at 40, 80, 160, 320, and 480 mg/m2 once per day for 28 days. At the end of the treatment cycle (Day 28), all patients with stable or improved disease could enter a long-term, follow-up period. To date, 12 patients have been treated, 11 completing the 28-day cycle. Forodesine is orally absorbed (40%–50%), mean terminal half-life of 12 to 20 h. dGuo levels were elevated in all patients (0.8–2.8 μM, predose levels ≤ 0.004 μM). Forodesine was generally safe and well tolerated in this population. Safety data is available for first 7 patients. No serious adverse events possibly related to the drug occurred. The most common adverse event possibly drug related was nausea (2 patients). Of the 11 patients completing the treatment cycle, 9 began long-term treatment. Of these 9 patients, 4 have received >3 months of treatment, while 1 patient continues to receive for >8 months. Efficacy data are available for 8 patients: 2 with partial response, 3 with minor response, 2 with progressive disease, and 1 with stable disease (Table). Forodesine showed preliminary evidence of clinical activity in refractory CTCL patients. Additional clinical and pharmacodynamic data will be presented. Clinical and Pharmacodynamic Activity of Oral Forodesine In CTCL Patients Patient Diagnosis Dose (mg/m2) Treatment Plasma dGuo (Cmax, M) μ Clinical Response PR = partial response; MR = minor response; SD = stable disease; PD = progressive disease; N/A = not available 2001 Sezary syndrome (IVA) 40 Completed 0.6 PR 3001 Mycosis fungoides (IVB) 40 Completed 1.7 PD 3002 Mycosis fungoides (IIB) 40 Completed 1.2 MR 3003 Mycosis fungoides (IB) 80 Completed 1.2 MR 3004 Sezary syndrome (IVA) 80 Completed 1.0 MR 3005 Sezary syndrome 80 Completed 1.6 PD 2002 IIA 80 Completed 1.1 PR 2003 III 80 Completed 1.7 N/A 3006 Mycosis fungoides/Sezary syndrome (IVB) 160 Completed 2.8 SD 4001 III 320 Completed 1.8 N/A 1001 Mycosis fungoides (IB) 320 Completed 1.3 N/A 3012 Mycosis fungoides/Sezary syndrome (IVA vs B) 320 Not Completed N/A Not evaluable

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Characteristics and Survival of 29 Patients with Sezary Syndrome.

Blood ◽

10.1182/blood.v106.11.5587.5587 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5587-5587

Author(s):

Francesca Sampogna ◽

Marina Frontani ◽

Giannandrea Baliva ◽

Damiano Abeni ◽

Giuseppe A. Lombardo ◽

...

Keyword(s):

Survival Analysis ◽

Survival Time ◽

White Blood Cells ◽

Clinical History ◽

Sézary Syndrome ◽

Sezary Syndrome ◽

Term Survival ◽

Kaplan Meier

Abstract We created a relational database of patients with cutaneous T-cell lymphoma (CTCL) to collect in a standardised fashion, anagraphic variables, clinical history, clinical, histological, haematological, and immunological information on CTCL patients hospitalised at IDI-IRCCS, Rome, Italy. At present, there are data on 424 patients, hospitalised from 1983 to July 2005. Active follow-up is performed yearly to ensure a standardised ascertainment of survival time. For deceased patients, the actual date of death (for all causes) is recorded, while surviving patients are censored at the date of last contact. The database includes 29 patients with Sezary syndrome (SS). Follow-up times ranged from 0 to 105 months. At first hospitalisation the median values of cells/mL were: white blood cells (WBC) 8750, neutrophils 4250, eosinophils 140, basophils 120, lymphocytes 2760, monocytes 500, CD3+ 2780, CD4+ 2431, CD8+ 192, CD19+ 96. Seventeen patients were deceased. We included in the Kaplan-Meier survival analysis only patients who were diagnosed before July 2004 (n=26). Median survival time from diagnosis was 52 months. No significant differences were observed in mortality for WBC (cutoff 9000 cells/uL), neutrophils (cutoff 4500 cells/uL), basophils (cutoff 200 cells/uL), lymphocytes (cutoff 3000 cells/uL), monocytes (cutoff 500 cells/uL), CD3+ (cutoff 2000 cells/uL), CD4+ (cutoff 2000 cells/uL), CD8+ (cutoff 200 cells/uL), CD19+ (cutoff 70 cells/uL). A lower survival was observed for patients with eosinophils <200 cells/uL (p=.08). Survival in patients with SS does not seem to be influenced by haemathologic parameters. However, patients with long-term survival (>90 months) are observed, and their characteristics should be further investigated. Survival analysis of 26 patients with Sézary syndrome, Rome, Italy, 1991–2004. Survival analysis of 26 patients with Sézary syndrome, Rome, Italy, 1991–2004.

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Long-term Outcomes of 1,263 Patients with Mycosis Fungoides and Sézary Syndrome from 1982 to 2009

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-12-0604 ◽

2012 ◽

Vol 18 (18) ◽

pp. 5051-5060 ◽

Cited By ~ 160

Author(s):

Rakhshandra Talpur ◽

Lotika Singh ◽

Seema Daulat ◽

Ping Liu ◽

Sarah Seyfer ◽

...

Keyword(s):

Mycosis Fungoides ◽

Sézary Syndrome ◽

Sezary Syndrome ◽

Long Term Outcomes

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A Long-Term Study of Persistent Sézary Syndrome

American Journal of Dermatopathology ◽

10.1097/dad.0000000000001637 ◽

2020 ◽

Vol 42 (6) ◽

pp. 389-396

Author(s):

Jenny C. Hoffmann ◽

Susan K. Atwater ◽

Eric Hong ◽

Jyoti Kumar ◽

Michael Khodadoust ◽

...

Keyword(s):

Sézary Syndrome ◽

Sezary Syndrome ◽

Term Study ◽

Long Term Study

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Xenograft and cell culture models of Sézary syndrome reveal cell of origin diversity and subclonal heterogeneity

Leukemia ◽

10.1038/s41375-020-01068-2 ◽

2020 ◽

Author(s):

Sandrine Poglio ◽

Martina Prochazkova-Carlotti ◽

Floriane Cherrier ◽

Audrey Gros ◽

Elodie Laharanne ◽

...

Keyword(s):

T Cell ◽

Clonal Selection ◽

Culture Conditions ◽

Response To Therapy ◽

Sézary Syndrome ◽

Sezary Syndrome ◽

Cell Of Origin ◽

Percutaneous Injection ◽

Defined Culture

Abstract Sézary Syndrome (SS) is a rare aggressive epidermotropic cutaneous T-cell lymphoma (CTCL) defined by erythroderma, pruritis, and a circulating atypical CD4 + T-cell clonal population. The diversity of Sézary cell (SC) phenotype and genotype may reflect either plasticity or heterogeneity, which was difficult to evaluate dynamically until the achievement of long-term SC expansion. Therefore, we developed six defined culture conditions allowing for the expansion of SC defined by their phenotype and monoclonality in four of seven SS cases. Engraftment of SC through the intrafemoral route into immunodeficient NOD.Cg-Prkdc(scid)Il2rg(tm1Wjll)/SzJ (NSG) mice was achieved in 2 of 14 SS cases. Secondary xenograft by percutaneous injection mimicked most of the features of SS with dermal infiltration, epidermotropism, and blood spreading. These models also allowed assessing the intra-individual heterogeneity of patient SC. Subclones sharing the same TCR gene rearrangement evolved independently according to culture conditions and/or after xenografting. This clonal selection was associated with some immunophenotypic plasticity and limited genomic evolution both in vitro and in vivo. The long-term amplification of SC allowed us to develop eight new SC lines derived from four different patients. These lines represent the cell of origin diversity of SC and provide new tools to evaluate their functional hallmarks and response to therapy.

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