T-cell large granular lymphocyte leukemia

Summary

T-cell large granular lymphocyte leukemia (MONDO:0019469) is a cancer with 1 cohort gene (1 CIViC-evidence somatic driver) and 55 clinical trials. Top therapeutic interventions include foscarnet, alemtuzumab, and bendamustine hydrochloride.

At a glance

• Classification: Cancer
• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 1
• Clinical trials: 55

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.4	Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	T-cell large granular lymphocyte leukemia
Mondo ID	MONDO:0019469
Orphanet	86872
DOID	DOID:0050751
ICD-11	83430037
NCIT	C4664
SNOMED CT	277569004
UMLS	C1955861
MedGen	363038
GARD	0009812
MedDRA	10065862
Is cancer (heuristic)	yes

Also known as: large cell granular lymphogenous leukaemia · large cell granular lymphogenous leukemia · large cell granular lymphoid leukaemia · large cell granular lymphoid leukemia · large granular lymphocyte leukaemia · large granular lymphocyte leukemia · large granular lymphocytic leukemia · large granular lymphocytosis · leukemia, large granular LYMPHOCYTIC, malignant · LGL leukaemia · LGL leukemia · LGLL · proliferation of large granular lymphocytes · T gamma lymphoproliferative disorder · T-cell large gran. lymph. leuk. · T-cell large granular lymphocyte leukemia · T-cell large granular lymphocytic leukaemia · T-cell large granular lymphocytic leukemia · T-cell LGL leukaemia · T-cell LGL leukemia (+7 more)

Data availability: 3 cell lines.

Disease family

Classification path: disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › hematopoietic and lymphoid system neoplasm › hematopoietic and lymphoid cell neoplasm › lymphoid neoplasm › T-cell and NK-cell neoplasm › neoplasm of mature T-cells or NK-cells › mature T-cell and NK-cell non-Hodgkin lymphoma › T-cell large granular lymphocyte leukemia

Related subtypes (7): angioimmunoblastic T-cell lymphoma, systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood, hydroa vacciniforme-like lymphoma, T-cell prolymphocytic leukemia, aggressive NK-cell leukemia, anaplastic large cell lymphoma, breast implant-associated anaplastic large 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
STAT3	Act	DLBCLNOS,LNM,MLYM,NHL	CIViC #5516

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STAT3	Orphanet:2314	Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency
STAT3	Orphanet:438159	STAT3-related early-onset multisystem autoimmune disease
STAT3	Orphanet:512017	Chronic lymphoproliferative disorder of natural killer cells
STAT3	Orphanet:520	Acute promyelocytic leukemia
STAT3	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
STAT3	Orphanet:86872	T-cell large granular lymphocyte leukemia
STAT3	Orphanet:99885	Isolated permanent neonatal diabetes mellitus

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STAT3	HGNC:11364	ENSG00000168610	P40763	Signal transducer and activator of transcription 3	civic_evidence

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STAT3	Signal transducer and activator of transcription 3	Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STAT3	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf

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
lower lobe of lung	1
pericardium	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STAT3	301	ubiquitous	marker	type B pancreatic cell, pericardium, lower lobe of lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STAT3	10,108

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STAT3	P40763	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 76. 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
Signalling to STAT3	1	3806.7×	0.005	STAT3
MET activates STAT3	1	3806.7×	0.005	STAT3
PTK6 Activates STAT3	1	2855.0×	0.005	STAT3
Signaling by PDGFR in disease	1	1631.4×	0.005	STAT3
Interleukin-6 family signaling	1	1427.5×	0.005	STAT3
BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members	1	1268.9×	0.005	STAT3
Interleukin-9 signaling	1	1268.9×	0.005	STAT3
Interleukin-23 signaling	1	1268.9×	0.005	STAT3
FGFR1 mutant receptor activation	1	1142.0×	0.005	STAT3
Interleukin-21 signaling	1	1142.0×	0.005	STAT3
Signaling by KIT in disease	1	1142.0×	0.005	STAT3
Signaling by Leptin	1	1038.2×	0.005	STAT3
Interleukin-27 signaling	1	1038.2×	0.005	STAT3
STAT3 nuclear events downstream of ALK signaling	1	1038.2×	0.005	STAT3
Interleukin-6 signaling	1	951.7×	0.005	STAT3
Interleukin-35 Signalling	1	951.7×	0.005	STAT3
POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation	1	878.5×	0.005	STAT3
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	878.5×	0.005	STAT3
Signaling by PDGFRA extracellular domain mutants	1	878.5×	0.005	STAT3
Interleukin-15 signaling	1	761.3×	0.005	STAT3
Signaling by cytosolic FGFR1 fusion mutants	1	634.4×	0.005	STAT3
Interleukin-2 family signaling	1	634.4×	0.005	STAT3
Signaling by ALK	1	571.0×	0.005	STAT3
Signaling by CSF3 (G-CSF)	1	571.0×	0.005	STAT3
Transcriptional regulation of pluripotent stem cells	1	543.8×	0.005	STAT3
Signaling by PTK6	1	543.8×	0.005	STAT3
Signaling by Non-Receptor Tyrosine Kinases	1	543.8×	0.005	STAT3
Interleukin-37 signaling	1	519.1×	0.005	STAT3
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	519.1×	0.005	STAT3
Interleukin-12 family signaling	1	475.8×	0.005	STAT3

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 growth factor dependent skeletal muscle satellite cell proliferation	1	8426.0×	0.003	STAT3
eye photoreceptor cell differentiation	1	4213.0×	0.003	STAT3
negative regulation of hydrogen peroxide biosynthetic process	1	4213.0×	0.003	STAT3
negative regulation of primary miRNA processing	1	4213.0×	0.003	STAT3
interleukin-11-mediated signaling pathway	1	3370.4×	0.003	STAT3
T-helper 17 type immune response	1	3370.4×	0.003	STAT3
postsynapse to nucleus signaling pathway	1	3370.4×	0.003	STAT3
interleukin-23-mediated signaling pathway	1	2808.7×	0.003	STAT3
regulation of cellular response to hypoxia	1	2808.7×	0.003	STAT3
leptin-mediated signaling pathway	1	2407.4×	0.003	STAT3
response to leptin	1	2407.4×	0.003	STAT3
cellular response to interleukin-17	1	2407.4×	0.003	STAT3
interleukin-2-mediated signaling pathway	1	2106.5×	0.003	STAT3
interleukin-9-mediated signaling pathway	1	2106.5×	0.003	STAT3
retinal rod cell differentiation	1	1872.4×	0.003	STAT3
regulation of feeding behavior	1	1872.4×	0.003	STAT3
interleukin-15-mediated signaling pathway	1	1685.2×	0.003	STAT3
negative regulation of inflammatory response to wounding	1	1685.2×	0.003	STAT3
cellular response to leptin stimulus	1	1532.0×	0.003	STAT3
radial glial cell differentiation	1	1532.0×	0.003	STAT3
growth hormone receptor signaling pathway via JAK-STAT	1	1532.0×	0.003	STAT3
T-helper 17 cell lineage commitment	1	1532.0×	0.003	STAT3
regulation of mitochondrial membrane permeability	1	1404.3×	0.003	STAT3
interleukin-10-mediated signaling pathway	1	1404.3×	0.003	STAT3
negative regulation of neuron migration	1	1404.3×	0.003	STAT3
growth hormone receptor signaling pathway	1	1203.7×	0.003	STAT3
positive regulation of extracellular matrix disassembly	1	1203.7×	0.003	STAT3
positive regulation of ATP biosynthetic process	1	1203.7×	0.003	STAT3
interleukin-6-mediated signaling pathway	1	1123.5×	0.003	STAT3
negative regulation of glycolytic process	1	1053.2×	0.003	STAT3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
STAT3	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STAT3	18	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	STAT3
NITAZOXANIDE	4	STAT3
NICLOSAMIDE	4	STAT3
DIGOXIN	4	STAT3
BARICITINIB	4	STAT3
DIGITOXIN	4	STAT3
DEUCRAVACITINIB	4	STAT3
CURCUMIN	3	STAT3
BARDOXOLONE METHYL	3	STAT3
NIFUROXAZIDE	3	STAT3
DELGOCITINIB	3	STAT3
LESTAURTINIB	3	STAT3
NAPABUCASIN	3	STAT3
LEVOMENOL	2	STAT3
AZD-1480	2	STAT3
WP 1066	2	STAT3
C-188-9	2	STAT3
GENISTEIN	2	STAT3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
STAT3	1,319	Binding:1304, Functional:12, Unclassified:2, ADMET:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
STAT3	1,319

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).

Drug repurposing candidates

18 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
MOMELOTINIB	4	STAT3
NITAZOXANIDE	4	STAT3
NICLOSAMIDE	4	STAT3
DIGOXIN	4	STAT3
BARICITINIB	4	STAT3
DIGITOXIN	4	STAT3
DEUCRAVACITINIB	4	STAT3
CURCUMIN	3	STAT3
BARDOXOLONE METHYL	3	STAT3
NIFUROXAZIDE	3	STAT3
DELGOCITINIB	3	STAT3
LESTAURTINIB	3	STAT3
NAPABUCASIN	3	STAT3
LEVOMENOL	2	STAT3
AZD-1480	2	STAT3
WP 1066	2	STAT3
C-188-9	2	STAT3
GENISTEIN	2	STAT3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	STAT3
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 55.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	17
PHASE1	17
Not specified	11
PHASE1/PHASE2	7
EARLY_PHASE1	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04453345	PHASE2/PHASE3	UNKNOWN	TPM Regimen (Thalidomide, Prednisone and Methotrexate) in LGLL
NCT05141682	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Oral Azacitidine for the Treatment of Relapsed or Refractory T-cell Large Granular Lymphocytic Leukemia
NCT05592015	PHASE2	RECRUITING	Ruxolitinib for the Treatment of T-Cell Large Granular Lymphocytic Leukemia
NCT06530550	PHASE2	RECRUITING	PI3K Inhibitors for the Treatment of Relapsed/Refractory Indolent T/NK-cell Lymphomas
NCT06530576	PHASE2	RECRUITING	Thalidomide for the Symptomatic Large Granular Lymphocytic Leukemia
NCT06716658	PHASE2	RECRUITING	JAK1 Inhibitor Golidocitnib for the Treatment of Relapsed/Refractory Indolent T/NK-cell Lymphomas
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
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
NCT00104858	PHASE2	COMPLETED	Fludarabine Phosphate, Radiation Therapy, and Rituximab in Treating Patients Who Are Undergoing Donor Stem Cell Transplant Followed by Rituximab for High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
NCT00278265	PHASE2	TERMINATED	Methotrexate Followed by Fludarabine in Patients With T-Cell Large Granular Lymphocytic Leukemia
NCT00360776	PHASE2	TERMINATED	Tipifarnib in Treating Patients With Anemia or Neutropenia and Large Granular Lymphocyte Leukemia
NCT00363779	PHASE2	TERMINATED	Effect of Cyclosporine Therapy on Gene Expression in Patients With Large Granular Lymphocyte Leukemia
NCT00387426	PHASE2	TERMINATED	Sunitinib in Treating Patients With Idiopathic Myelofibrosis
NCT01093586	PHASE2	COMPLETED	Donor Umbilical Cord Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01258998	PHASE2	COMPLETED	Study of Akt Inhibitor MK2206 in Patients With Relapsed Lymphoma
NCT01384513	PHASE2	COMPLETED	A Two-Step Approach to Reduced Intensity Bone Marrow Transplant for Patients With Hematological Malignancies
NCT01419795	PHASE2	TERMINATED	Lenalidomide With or Without Rituximab in Treating Patients With Progressive or Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Prolymphocytic Leukemia, or Non-Hodgkin Lymphoma Previously Treated With Donor Stem Cell Transplant
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01652014	PHASE2	WITHDRAWN	Single or Double Donor Umbilical Cord Blood Transplant in Treating Patients With High-Risk Hematologic Malignancies
NCT01805037	PHASE1/PHASE2	TERMINATED	Brentuximab Vedotin + Rituximab as Frontline Therapy for Pts w/ CD30+ and/or EBV+ Lymphomas
NCT01839916	PHASE2	COMPLETED	Donor T Cells After Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT02742727	PHASE1/PHASE2	UNKNOWN	CAR-pNK Cell Immunotherapy in CD7 Positive Leukemia and Lymphoma
NCT03239392	PHASE1/PHASE2	COMPLETED	A Dose-Ranging Study of IV BNZ-1 in LGL Leukemia or Refractory CTCL
NCT05532722	PHASE1/PHASE2	COMPLETED	ABC008 in Subjects With T-cell Large Granular Lymphocytic Leukemia (T-LGLL)
NCT05010005	PHASE1	RECRUITING	A Study of Ruxolitinib and Duvelisib in People With Lymphoma
NCT00025415	PHASE1	COMPLETED	Imatinib Mesylate in Treating Patients With Advanced Cancer and Liver Dysfunction
NCT00076180	PHASE1	COMPLETED	Hu-Mik-beta1 to Treat T-Cell Large Granular Lymphocytic Leukemia
NCT00101205	PHASE1	TERMINATED	Oxaliplatin, Ifosfamide and Etoposide in Treating Young Patients With Recurrent or Refractory Solid Tumors or Lymphoma
NCT00458731	PHASE1	COMPLETED	Bevacizumab and Cediranib Maleate in Treating Patients With Metastatic or Unresectable Solid Tumor, Lymphoma, Intracranial Glioblastoma, Gliosarcoma or Anaplastic Astrocytoma
NCT00608361	PHASE1	COMPLETED	Dasatinib in Treating Patients With Solid Tumors or Lymphomas That Are Metastatic or Cannot Be Removed By Surgery
NCT00890747	PHASE1	COMPLETED	Sunitinib Malate in Treating HIV-Positive Patients With Cancer Receiving Antiretroviral Therapy
NCT01088763	PHASE1	TERMINATED	Gamma-Secretase Inhibitor RO4929097 in Treating Young Patients With Relapsed or Refractory Solid Tumors, CNS Tumors, Lymphoma, or T-Cell Leukemia
NCT01129180	PHASE1	COMPLETED	Bortezomib and Azacitidine in Treating Patients With Relapsed or Refractory T-Cell Lymphoma
NCT01254578	PHASE1	COMPLETED	Lenalidomide After Donor Bone Marrow Transplant in Treating Patients With High-Risk Hematologic Cancers
NCT01567709	PHASE1	COMPLETED	Alisertib in Combination With Vorinostat in Treating Patients With Relapsed or Recurrent Hodgkin Lymphoma, B-Cell Non-Hodgkin Lymphoma, or Peripheral T-Cell Lymphoma
NCT01588015	PHASE1	COMPLETED	Vaccine Therapy in Preventing Cytomegalovirus Infection in Patients With Hematological Malignancies Undergoing Donor Stem Cell Transplant
NCT01678443	PHASE1	TERMINATED	Monoclonal Antibody Therapy Before Stem Cell Transplant in Treating Patients With Relapsed or Refractory Lymphoid Malignancies
NCT01748721	PHASE1	COMPLETED	MORAb-004 in Treating Young Patients With Recurrent or Refractory Solid Tumors or Lymphoma
NCT01769222	PHASE1	TERMINATED	Ipilimumab and Local Radiation for Selected Solid Tumors

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FOSCARNET	4	4
ALEMTUZUMAB	4	1
BENDAMUSTINE HYDROCHLORIDE	4	1
BRENTUXIMAB VEDOTIN	4	1
DUVELISIB	4	1
FILGRASTIM	4	1
GANCICLOVIR	4	1
SILTUXIMAB	4	1
SUNITINIB MALATE	4	1
THALIDOMIDE	4	1
VALGANCICLOVIR	4	1
6-O-BENZYLGUANINE	3	1
ALISERTIB	3	1
CEDIRANIB MALEATE	3	1
CPI 613	3	1
TIPIFARNIB	3	1
ULVIPRUBART	2	1
CHEMBL15720	0	1
CHEMBL426123	0	1
CHEMBL3109278	0	1
CHEMBL3805348	0	1
CHEMBL4538684	0	1