Sezary syndrome

Summary

Sezary syndrome (MONDO:0017844) is a disease with 1 cohort gene and 134 clinical trials. Molecularly, CTLA4::CD28 Fusion confers sensitivity to Ipilimumab in Sezary’s Disease (CIViC Level C). Top therapeutic interventions include mogamulizumab, brentuximab vedotin, and foscarnet.

At a glance

• Prevalence: <1 / 1 000 000 (United States) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 29
• Clinical trials: 134
• Precision-medicine evidence (CIViC): 1 subtype–drug association

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.02	United States	Validated
Annual incidence	<1 / 1 000 000	0.012	Norway	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0000958	Dry skin	Very frequent (80-99%)
HP:0000989	Pruritus	Very frequent (80-99%)
HP:0001019	Erythroderma	Very frequent (80-99%)
HP:0002665	Lymphoma	Very frequent (80-99%)
HP:0002716	Lymphadenopathy	Very frequent (80-99%)
HP:0002843	Abnormal T cell morphology	Very frequent (80-99%)
HP:0004332	Abnormal lymphocyte morphology	Very frequent (80-99%)
HP:0008069	Neoplasm of the skin	Very frequent (80-99%)
HP:0012192	Cutaneous T-cell lymphoma	Very frequent (80-99%)
HP:0100725	Lichenification	Very frequent (80-99%)
HP:0000982	Palmoplantar keratoderma	Frequent (30-79%)
HP:0001596	Alopecia	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002721	Immunodeficiency	Frequent (30-79%)
HP:0008404	Nail dystrophy	Frequent (30-79%)
HP:0033221	Increased CD4:CD8 ratio	Frequent (30-79%)
HP:0000656	Ectropion	Occasional (5-29%)
HP:0000969	Edema	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0002045	Hypothermia	Occasional (5-29%)
HP:0002103	Abnormality of the pleura	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0007400	Irregular hyperpigmentation	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0010701	Abnormal immunoglobulin level	Occasional (5-29%)
HP:0025143	Chills	Occasional (5-29%)
HP:0025144	Shivering	Occasional (5-29%)
HP:0100758	Gangrene	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Sezary syndrome
Mondo ID	MONDO:0017844
EFO	EFO:1000785
MeSH	D012751
Orphanet	3162
DOID	DOID:8541
ICD-11	1358020385
NCIT	C3366
SNOMED CT	118611004
UMLS	C0036920
MedGen	19959
GARD	0007629
MedDRA	10040493, 10040500
NORD	1707
Is cancer (heuristic)	no

Also known as: CTCL / Sezary syndrome · cutaneous T-cell lymphoma/Sezary syndrome · SC)zary syndrome · Sezary disease · Sezary lymphoma · Sezary syndrome · Sezary’s disease · Sezary’s lymphoma · SS · Sézary lymphoma · Sézary syndrome

Data availability: 1 ClinVar variant · 38 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › integumentary system cancer › skin cancer › primary cutaneous lymphoma › primary cutaneous T-cell non-Hodgkin lymphoma › Sezary syndrome

Related subtypes (4): mycosis fungoides, primary cutaneous anaplastic large cell lymphoma, mycosis fungoides variant, primary cutaneous gamma-delta t-cell lymphoma

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
6260	NM_003921.5(BCL10):c.428del (p.Phe143fs)	BCL10	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BCL10	Orphanet:52417	MALT lymphoma

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BCL10	HGNC:989	ENSG00000142867	O95999	B-cell lymphoma/leukemia 10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BCL10	B-cell lymphoma/leukemia 10	Plays a key role in both adaptive and innate immune signaling by bridging CARD domain-containing proteins to immune activation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BCL10	Other/Unknown	no		CARD, DEATH-like_dom_sf, BCL10/E10

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
esophagus squamous epithelium	1
mucosa of sigmoid colon	1
squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BCL10	280	ubiquitous	marker	esophagus squamous epithelium, mucosa of sigmoid colon, squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BCL10	1,873

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BCL10	O95999	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Downstream signaling events of B Cell Receptor (BCR)	1	815.7×	0.010	BCL10
Protein ubiquitination	1	815.7×	0.010	BCL10
TCR signaling	1	496.5×	0.010	BCL10
Signaling by the B Cell Receptor (BCR)	1	346.1×	0.010	BCL10
Fc epsilon receptor (FCERI) signaling	1	271.9×	0.010	BCL10
C-type lectin receptors (CLRs)	1	237.9×	0.010	BCL10
Activation of NF-kappaB in B cells	1	196.9×	0.010	BCL10
E3 ubiquitin ligases ubiquitinate target proteins	1	193.6×	0.010	BCL10
FCERI mediated NF-kB activation	1	156.4×	0.011	BCL10
CLEC7A (Dectin-1) signaling	1	142.8×	0.011	BCL10
Downstream TCR signaling	1	128.3×	0.011	BCL10
Adaptive Immune System	1	29.8×	0.045	BCL10
Innate Immune System	1	25.5×	0.048	BCL10
Post-translational protein modification	1	19.2×	0.060	BCL10
Immune System	1	13.0×	0.081	BCL10
Metabolism of proteins	1	12.4×	0.081	BCL10

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of lymphotoxin A production	1	5617.3×	0.003	BCL10
negative regulation of mature B cell apoptotic process	1	4213.0×	0.003	BCL10
positive regulation of mast cell cytokine production	1	3370.4×	0.003	BCL10
quinolinate biosynthetic process	1	1532.0×	0.004	BCL10
B cell apoptotic process	1	1404.3×	0.004	BCL10
programmed cell death	1	1296.3×	0.004	BCL10
T cell apoptotic process	1	1296.3×	0.004	BCL10
antifungal innate immune response	1	936.2×	0.004	BCL10
non-canonical NF-kappaB signal transduction	1	842.6×	0.004	BCL10
positive regulation of phosphorylation	1	842.6×	0.004	BCL10
positive regulation of T cell receptor signaling pathway	1	766.0×	0.004	BCL10
immunoglobulin mediated immune response	1	702.2×	0.004	BCL10
toll-like receptor signaling pathway	1	601.9×	0.004	BCL10
lipopolysaccharide-mediated signaling pathway	1	526.6×	0.004	BCL10
response to food	1	495.6×	0.004	BCL10
positive regulation of extrinsic apoptotic signaling pathway	1	455.5×	0.004	BCL10
positive regulation of T cell activation	1	443.5×	0.004	BCL10
cellular defense response	1	318.0×	0.006	BCL10
positive regulation of interleukin-8 production	1	244.2×	0.007	BCL10
apoptotic signaling pathway	1	224.7×	0.007	BCL10
cellular response to mechanical stimulus	1	216.1×	0.007	BCL10
positive regulation of protein ubiquitination	1	213.3×	0.007	BCL10
obsolete positive regulation of NF-kappaB transcription factor activity	1	205.5×	0.007	BCL10
neural tube closure	1	187.2×	0.007	BCL10
positive regulation of interleukin-6 production	1	166.8×	0.008	BCL10
T cell receptor signaling pathway	1	151.8×	0.008	BCL10
protein homooligomerization	1	122.1×	0.010	BCL10
cellular response to lipopolysaccharide	1	98.0×	0.012	BCL10
adaptive immune response	1	84.3×	0.014	BCL10
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.015	BCL10

Therapeutics

Drugs indicated for this disease

1 approved, 2 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Mogamulizumab	Approved (phase 4)
Naloxone	Phase 3 (in late-stage trials)
Zanolimumab	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Alemtuzumab, Atezolizumab, Bexarotene, Brentuximab Vedotin, Fludarabine Phosphate, INTERFERON GAMMA-1B, Melphalan, Methotrexate, Methoxsalen, Mycophenolate Mofetil, Nelarabine, Pembrolizumab, Ritlecitinib, Rosiglitazone, Tacrolimus Anhydrous, Vorinostat.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BCL10	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BCL10

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
BCL10	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 134.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	43
PHASE1	41
Not specified	29
PHASE1/PHASE2	13
PHASE4	3
EARLY_PHASE1	3
PHASE3	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00050999	PHASE4	COMPLETED	Study of ONTAK (Denileukin Diftitox) in Cutaneous T-Cell Lymphoma (CTCL) Patients
NCT00051012	PHASE4	COMPLETED	Study of ONTAK (Denileukin Diftitox) in Previously Treated Cutaneous T-Cell Lymphoma Patients
NCT01625455	PHASE4	TERMINATED	Effect of Neurokinin-1 Receptor (NK1R) Antagonism on Pruritus in Patients With Sezary Syndrome
NCT00127881	PHASE3	TERMINATED	Study of Human Monoclonal Antibody to Treat Mycosis Fungoides and Sezary Syndrome
NCT02811783	PHASE3	TERMINATED	Naloxone Hydrochloride Study for Relief of Pruritus in Patients With MF or SS Forms of CTCL
NCT02978625	PHASE2	ACTIVE_NOT_RECRUITING	Talimogene Laherparepvec and Nivolumab in Treating Patients With Refractory Lymphomas or Advanced or Refractory Non-melanoma Skin Cancers
NCT03011814	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Durvalumab With or Without Lenalidomide in Treating Patients With Relapsed or Refractory Cutaneous or Peripheral T Cell Lymphoma
NCT03587844	PHASE2	RECRUITING	Dosing of Brentuximab Vedotin for Mycosis Fungoides, Sezary Syndrome Patients
NCT04256018	PHASE2	RECRUITING	Mogamulizumab + Low-Dose Total Skin Electron Beam Tx in Mycosis Fungoides & Sézary Syndrome
NCT04930653	PHASE2	RECRUITING	Extracorporeal Photopheresis and Mogamulizumab for the Treatment of Erythrodermic Cutaneous T Cell Lymphoma
NCT04960618	PHASE2	ACTIVE_NOT_RECRUITING	Pembrolizumab in Combination With Gemcitabine in People With Advanced Mycosis Fungoides or Sézary Syndrome
NCT07535710	PHASE1/PHASE2	NOT_YET_RECRUITING	Aclarubicin Plus Cyclophosphamide, Vincristine, and Prednisone (CAOP) in Patients With Previously Treated Cutaneous T-cell Lymphoma
NCT00003210	PHASE2	COMPLETED	Interleukin-12 in Treating Patients With Previously Treated Non-Hodgkin’s Lymphoma or Hodgkin’s Disease
NCT00005080	PHASE2	COMPLETED	506U78 in Treating Patients With Lymphoma
NCT00005982	PHASE2	TERMINATED	506U78 in Treating Patients With Recurrent or Refractory Cutaneous T-cell Lymphoma
NCT00006251	PHASE1/PHASE2	COMPLETED	Fludarabine Phosphate, Low-Dose Total-Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine, Mycophenolate Mofetil, Donor Lymphocyte Infusion in Treating Patients With Hematopoietic Cancer
NCT00040846	PHASE2	COMPLETED	Alemtuzumab, Fludarabine Phosphate, and Low-Dose Total Body Irradiation Before Donor Stem Cell Transplantation in Treating Patients With Hematological Malignancies
NCT00047060	PHASE1/PHASE2	COMPLETED	Stem Cell Transplant Therapy With Campath-1H for Treating Advanced Mycosis Fungoides and Sezary Syndrome
NCT00049504	PHASE2	COMPLETED	Haploidentical Donor Bone Marrow Transplant in Treating Patients With High-Risk Hematologic Cancer
NCT00052377	PHASE1/PHASE2	TERMINATED	Interleukin-12 and Interleukin-2 in Treating Patients With Mycosis Fungoides
NCT00072514	PHASE2	COMPLETED	Gemcitabine Hydrochloride, Carboplatin, Dexamethasone, and Rituximab in Treating Patients With Previously Treated Lymphoid Malignancies
NCT00078858	PHASE1/PHASE2	COMPLETED	Mycophenolate Mofetil and Cyclosporine in Reducing Graft-Versus-Host Disease in Patients With Hematologic Malignancies or Metastatic Kidney Cancer Undergoing Donor Stem Cell Transplant
NCT00089011	PHASE2	COMPLETED	Tacrolimus and Mycophenolate Mofetil in Preventing Graft-Versus-Host Disease in Patients Who Have Undergone Total-Body Irradiation With or Without Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant for Hematologic Cancer
NCT00091559	PHASE2	COMPLETED	Oral SAHA (Suberoylanilide Hydroxamic Acid) in Advanced Cutaneous T-cell Lymphoma (0683-001)
NCT00099593	PHASE2	COMPLETED	Immunization Against Tumor Cells in Sezary Syndrome
NCT00112723	PHASE1/PHASE2	TERMINATED	Flavopiridol in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma
NCT00118352	PHASE2	COMPLETED	Alemtuzumab, Fludarabine Phosphate, and Total-Body Irradiation Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer
NCT00157274	PHASE2	UNKNOWN	Study of Alemtuzumab to Treat Advanced Mycosis Fungoides/Sezary Syndrome
NCT00178841	PHASE2	COMPLETED	Combination Drug Study of Bexarotene and Rosiglitazone to Treat CTCL
NCT00489203	PHASE2	COMPLETED	Beclomethasone Dipropionate in Preventing Acute Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer
NCT00601718	PHASE1/PHASE2	COMPLETED	Vorinostat, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Lymphoma or Previously Untreated T-Cell Non-Hodgkin Lymphoma or Mantle Cell Lymphoma
NCT00611208	PHASE2	COMPLETED	A-dmDT390-bisFv(UCHT1) Immunotoxin Therapy for Patients With Cutaneous T-Cell Lymphoma (CTCL)
NCT00795769	PHASE2	COMPLETED	Ondansetron in Preventing Nausea and Vomiting in Patients Undergoing Stem Cell Transplant
NCT00896493	PHASE2	COMPLETED	Ph II of Non-myeloablative Allogeneic Transplantation Using TLI & ATG In Patients w/ Cutaneous T Cell Lymphoma
NCT00918333	PHASE1/PHASE2	COMPLETED	Panobinostat and Everolimus in Treating Patients With Recurrent Multiple Myeloma, Non-Hodgkin Lymphoma, or Hodgkin Lymphoma
NCT01044745	PHASE2	TERMINATED	Rituximab in Preventing Acute Graft-Versus-Host Disease in a Donor Stem Cell Transplant for Hematologic Cancer
NCT01075321	PHASE1/PHASE2	COMPLETED	Everolimus and Lenalidomide in Treating Patients With Relapsed or Refractory Non-Hodgkin or Hodgkin Lymphoma
NCT01093586	PHASE2	COMPLETED	Donor Umbilical Cord Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01110135	PHASE2	COMPLETED	Bendamustine Hydrochloride, Etoposide, Dexamethasone, and Filgrastim For Peripheral Blood Stem Cell Mobilization in Treating Patients With Refractory or Recurrent Lymphoma or Multiple Myeloma
NCT01159067	PHASE2	TERMINATED	Deferasirox for Treating Patients Who Have Undergone Allogeneic Stem Cell Transplant and Have Iron Overload

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MOGAMULIZUMAB	4	6
BRENTUXIMAB VEDOTIN	4	5
FOSCARNET	4	4
ALEMTUZUMAB	4	3
BENDAMUSTINE HYDROCHLORIDE	4	3
DEXRAZOXANE	4	3
BELINOSTAT	4	2
BEXAROTENE	4	2
DEFERASIROX	4	2
DENILEUKIN DIFTITOX	4	2
NELARABINE	4	2
PANOBINOSTAT	4	2
ROMIDEPSIN	4	2
ROSIGLITAZONE	4	2
APREPITANT	4	1
BECLOMETHASONE DIPROPIONATE	4	1
CAPECITABINE	4	1
CYANOCOBALAMIN	4	1
GANCICLOVIR	4	1
ISOTRETINOIN	4	1
LETERMOVIR	4	1
LITHIUM CARBONATE	4	1
METHOXSALEN	4	1
NALOXONE	4	1
PALIFERMIN	4	1
PRALATREXATE	4	1
RITLECITINIB	4	1
TALIMOGENE LAHERPAREPVEC	4	1
VALGANCICLOVIR	4	1
VORINOSTAT	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 1 predictive associations from 1 curated evidence items.

Molecular subtype	Therapy	Effect	Level	CIViC
CTLA4::CD28 Fusion	Ipilimumab	Sensitivity/Response	CIViC C	EID1520