Home / Deep Research / Aggressive NK-cell Leukemia

Aggressive NK-cell Leukemia

Aggressive NK-cell Leukemia (ANKL) — Comprehensive Disease Characteristics Report

2026-05-11
Falcon MONDO:0019470 Model: Edison Scientific Literature 29 citations

Aggressive NK-cell Leukemia (ANKL) — Comprehensive Disease Characteristics Report

Target Disease

  • Disease name: Aggressive NK-cell leukemia (ANKL)
  • Category: Mature NK-cell neoplasm; EBV-associated T/NK-cell neoplasia spectrum
  • MONDO ID: Not available from the retrieved sources in this run (needs dedicated ontology lookup outside the current evidence set).

Evidence summary table

Table (click to expand)
Domain Key points Quantitative data Key source (with year, journal) URL
Definition / classification ANKL is a rare, fulminant, systemic mature NK-cell neoplasm with acute presentation and grave prognosis; recent reviews note it remains recognized in modern WHO/ICC-era classification of mature T/NK-cell neoplasms. It is distinct from extranodal NK/T-cell lymphoma, though overlap exists in disseminated disease. (hussein2020aggressivenkcell pages 1-3, spaner2024casereportaggressive pages 1-2, ferry2024maturebt pages 8-10) Median age around 40 years in review cohorts; fewer than 500 cases reported overall in literature summaries. (hussein2020aggressivenkcell pages 1-3, spaner2024casereportaggressive pages 1-2) El Hussein et al., 2020, Cancers; Spaner et al., 2024, Frontiers in Hematology; Ferry et al., 2024, J Hematol Oncol https://doi.org/10.3390/cancers12102900
EBV association EBV is strongly associated with ANKL and is detectable in most cases by EBER; however, EBV-negative ANKL exists and can show similar clinicopathologic features. ANKL often sits within the spectrum of EBV-associated T/NK-cell lymphoproliferative diseases. (hussein2020genomicandimmunophenotypic pages 1-2, ishida2018aggressivenkcellleukemia pages 1-2, tang2017aggressivenkcellleukemia pages 1-2, hussein2020aggressivenkcell pages 3-5) ~90% EBV-driven in a 2024 case review; ~10% EBV-negative in older review; EBER positive in 9/12 cases in one clinicopathologic series. (spaner2024casereportaggressive pages 1-2, ishida2018aggressivenkcellleukemia pages 1-2, hussein2020genomicandimmunophenotypic pages 1-2) Hussein et al., 2020, Am J Surg Pathol; Ishida, 2018, Front Pediatr; Spaner et al., 2024, Front Hematol https://doi.org/10.1097/pas.0000000000001518
Typical presentation / phenotypes Common features include fever, constitutional symptoms, hepatosplenomegaly, liver dysfunction, leukemic blood picture, cytopenias, HLH/hemophagocytosis, DIC/coagulopathy, and multiorgan failure; nasal/skin lesions are less common than marrow, blood, liver, and spleen involvement. (hussein2020aggressivenkcell pages 1-3, ni2024clinicopathologicalfeaturesand pages 1-2, ishida2018aggressivenkcellleukemia pages 1-2, spaner2024casereportaggressive pages 1-2) HLH reported in ~60–90% in pediatric case literature summary; in one 12-case series, HLH in 2/12; common involved organs include marrow, peripheral blood, liver, spleen, lymph nodes. (ni2024clinicopathologicalfeaturesand pages 1-2, hussein2020genomicandimmunophenotypic pages 1-2) Ni et al., 2024, Turkish Journal of Pediatrics; El Hussein et al., 2020, Cancers; Ishida, 2018, Front Pediatr https://doi.org/10.24953/turkjpediatr.2024.5072
Diagnostic immunophenotype Characteristic phenotype is NK-lineage with surface CD3 negative and cytoplasmic CD3ε positive; typically CD56+, CD2+, CD94+, cytotoxic marker positive (granzyme B, TIA1, perforin), usually negative for CD4, CD5, CD57, TCR αβ/γδ, and often lacking KIR expression. Bone marrow involvement may be interstitial or sinusoidal/intrasinusoidal. (hussein2020genomicandimmunophenotypic pages 1-2, hussein2020aggressivenkcell pages 3-5, hussein2020genomicandimmunophenotypic pages 2-3) In one 12-case series: CD56+ 12/12, CD94+ 9/9, CD2+ 10/12, EBER+ 9/12; negative in all tested for surface CD3 12/12, CD5 11/11, CD57 9/9, TCRαβ 11/11, TCRγδ 11/11. Marrow ANKL fraction ranged 1.5% to 96.4%, median 22.5%. (hussein2020genomicandimmunophenotypic pages 1-2, hussein2020genomicandimmunophenotypic pages 2-3) El Hussein et al., 2020, Am J Surg Pathol https://doi.org/10.1097/pas.0000000000001518
Genetics / pathways Recurrent alterations cluster in JAK/STAT activation, epigenetic dysregulation, TP53/DNA-repair impairment, and RAS/MAPK signaling; IL10-STAT3-MYC biosynthetic axis and HACE1 hypermethylation have been implicated. (hussein2020aggressivenkcell pages 1-3, ishida2018aggressivenkcellleukemia pages 1-2, tang2017aggressivenkcellleukemia pages 1-2, dufva2018aggressivenaturalkillercell pages 3-4) Dufva et al.: STAT3 21%, RAS-MAPK genes 21%, DDX3X 29%, epigenetic modifiers 50%; copy-gain/mutation events affecting JAK2/STAT3/STAT5B also reported. Other summaries report TP53 34%, TET2 28%, CREBBP 21%, MLL2/KMT2D 21%, JAK-STAT pathway alterations ~48%, STAT3 mutations ~17%. (dufva2018aggressivenaturalkillercell pages 3-4, ishida2018aggressivenkcellleukemia pages 1-2, sumbly2022aggressivenaturalkiller pages 2-3) Dufva et al., 2018, Nat Commun; Ishida, 2018, Front Pediatr; Sumbly et al., 2022, Cureus https://doi.org/10.1038/s41467-018-03987-2
Epidemiology / demographics ANKL is very rare, with geographic enrichment in Asian and Central/South American populations; most patients are young to middle-aged adults, though pediatric and older adult cases occur. Male predominance is reported in some cohorts. (hussein2020aggressivenkcell pages 1-3, ishida2018aggressivenkcellleukemia pages 1-2, tang2017aggressivenkcellleukemia pages 1-2) Chinese multicenter cohort: age peak 21–30 years was 29.2% (33/113); male:female ratio nearly 2:1 in that decade. Western clinicopathologic series: median age 47.5 years, 9 men/3 women. (tang2017aggressivenkcellleukemia pages 1-2, hussein2020genomicandimmunophenotypic pages 1-2) Tang et al., 2017, Blood Cancer Journal; El Hussein et al., 2020, Am J Surg Pathol https://doi.org/10.1038/s41408-017-0021-z
Prognosis Prognosis is extremely poor without effective induction and consolidation; many reviews cite median survival under 2–3 months. A subacute subtype with prolonged prodrome may have better outcomes than classic fulminant ANKL. (hussein2020aggressivenkcell pages 1-3, ni2024clinicopathologicalfeaturesand pages 1-2, ishida2018aggressivenkcellleukemia pages 1-2, tang2017aggressivenkcellleukemia pages 1-2, spaner2024casereportaggressive pages 1-2) Median OS 55 days and 1-year survival 4.42% (5/113) in a large cohort; median survival 2 months in a 12-case Western series; review summaries report median survival <2 to <3 months. (tang2017aggressivenkcellleukemia pages 1-2, hussein2020genomicandimmunophenotypic pages 1-2, ni2024clinicopathologicalfeaturesand pages 1-2) Tang et al., 2017, Blood Cancer Journal; El Hussein et al., 2020, Am J Surg Pathol; Ni et al., 2024, Turkish Journal of Pediatrics https://doi.org/10.1038/s41408-017-0021-z
Treatment: asparaginase-based therapy Anthracycline-only approaches are generally ineffective; L-asparaginase/pegaspargase-containing regimens are the main active induction strategy. Regimens used include SMILE, AspaMetDex, L-GemOx, and related protocols. (ni2024clinicopathologicalfeaturesand pages 1-2, tang2017aggressivenkcellleukemia pages 1-2) In Tang et al., among 13 newly diagnosed patients treated with AspaMetDex alone: CR 30.77% (4/13), ORR 76.92% (10/13), median OS 115 days; grade 3–4 hematologic AEs in 53.84% (7/13). Ni et al. summarize chemotherapy CR rate as <36%. (tang2017aggressivenkcellleukemia pages 1-2, ni2024clinicopathologicalfeaturesand pages 1-2) Tang et al., 2017, Blood Cancer Journal; Ni et al., 2024, Turkish Journal of Pediatrics https://doi.org/10.1038/s41408-017-0021-z
Treatment: allo-HSCT / outcomes Allogeneic HSCT is the only modality consistently associated with durable survival in fit responders and is typically pursued after remission induction with asparaginase-based chemotherapy. (tang2017aggressivenkcellleukemia pages 1-2, ni2024clinicopathologicalfeaturesand pages 1-2) In Tang et al., 7 patients underwent allo-HSCT after CR; median time to transplant 73 days, median OS 300 days, 2-year OS 42.86% (3/7). Ni et al. summarize ~55.5% relapse/progression within 1 year after allo-HSCT. (tang2017aggressivenkcellleukemia pages 1-2, ni2024clinicopathologicalfeaturesand pages 1-2) Tang et al., 2017, Blood Cancer Journal; Ni et al., 2024, Turkish Journal of Pediatrics https://doi.org/10.1038/s41408-017-0021-z
Emerging / targeted therapy rationale Genomic profiling and drug sensitivity studies support investigation of JAK inhibitors, BCL2 inhibition, and immune checkpoint blockade in selected cases, especially where JAK/STAT activation or PD-L1 expression is present. These remain emerging rather than standard ANKL therapies. (hussein2020genomicandimmunophenotypic pages 1-2, hussein2020aggressivenkcell pages 1-3, dufva2018aggressivenaturalkillercell pages 3-4) pSTAT3 positivity in 3/8 and PD-L1 positivity in 2/8 in one immunophenotypic series; Dufva et al. found NK malignancies highly sensitive to JAK and BCL2 inhibition in drug profiling. (hussein2020genomicandimmunophenotypic pages 1-2, dufva2018aggressivenaturalkillercell pages 3-4) El Hussein et al., 2020, Am J Surg Pathol; Dufva et al., 2018, Nat Commun https://doi.org/10.1038/s41467-018-03987-2

Table: This table condenses core disease facts for aggressive NK-cell leukemia, including classification, EBV association, presentation, diagnostic phenotype, genomics, prognosis, and treatment outcomes. It is useful as a quick evidence-backed reference for building a disease knowledge base entry.

1. Disease information

1.1 Concise overview (current understanding)

Aggressive NK-cell leukemia (ANKL) is a rare, fulminant systemic malignancy of mature natural killer (NK) cells with acute presentation, frequent cytokine-driven inflammatory complications (e.g., HLH), and very poor survival without rapid disease control and consolidation. Reviews emphasize that its acute clinical syndrome overlaps with other entities (notably EBV-associated lymphoproliferative disorders and NK/T-cell lymphomas), complicating early recognition and resulting in delayed diagnosis and treatment. (hussein2020aggressivenkcell pages 1-3, spaner2024casereportaggressive pages 1-2)

Direct abstract quote (example): “Aggressive natural killer cell leukemia (ANKL) is a rare, aggressive hematologic malignancy which often presents as fulminant Epstein-Barr virus (EBV)- driven hemophagocytic lymphohistiocytosis (HLH).” (spaner2024casereportaggressive pages 1-2)

1.2 Key identifiers and ontologies

  • WHO/ICC framing: The current hematopathology ecosystem includes WHO-HAEM5 (2022) and ICC (2022); comparative reviews summarize entity families and naming across systems. A classification comparison review provides the context that WHO-HAEM5 and ICC are the operative modern frameworks for mature B/T/NK neoplasms, and that EBV-positive T/NK entities are explicitly treated as a family. (ferry2024maturebt pages 8-10)
  • ICD/MeSH/OMIM/Orphanet: Not extractable from the current retrieved evidence set; these require targeted queries to OMIM/Orphanet/MeSH.

1.3 Synonyms / alternative names

  • “Aggressive NK-cell leukemia” (most common)
  • “Aggressive NK-cell leukaemia” (UK spelling)
  • Some literature uses “aggressive NK-cell leukemia/lymphoma” in broader discussions of NK-cell malignancies. (ishida2018aggressivenkcellleukemia pages 1-2, NCT03623087 chunk 1)

1.4 Evidence source types in this report

2. Etiology

2.1 Disease causal factors

Epstein–Barr virus (EBV) association

ANKL is commonly EBV-associated, with EBER positivity in the majority of cases in multiple series, and many reviews describing EBV as a driver in ~90% of cases (though EBV-negative ANKL exists). (hussein2020genomicandimmunophenotypic pages 1-2, ishida2018aggressivenkcellleukemia pages 1-2, spaner2024casereportaggressive pages 1-2)

2.2 Risk factors

Note: Specific germline genetic susceptibility loci or robust environmental risk factors were not retrievable from the current evidence set.

2.3 Protective factors

No protective factors (genetic or environmental) were identified in the retrieved evidence.

2.4 Gene–environment interactions

Not established in retrieved evidence; EBV infection is a biological exposure interacting with host immune status and tumor genetics, but formal GxE data were not found here.

3. Phenotypes (clinical features)

3.1 Core phenotype spectrum

ANKL commonly presents with an acute systemic inflammatory and hematologic syndrome including: - Fever / constitutional symptoms (symptom) - Hepatosplenomegaly (clinical sign) - Cytopenias and leukemic blood picture (laboratory abnormality) - Liver dysfunction / acute liver injury (laboratory and organ phenotype) - Coagulopathy / DIC (laboratory abnormality, complication) - Hemophagocytic lymphohistiocytosis (HLH) (immune dysregulation syndrome) - Multiorgan failure in severe/refractory disease These are repeatedly highlighted across reviews, cohorts, and 2024 case literature. (hussein2020aggressivenkcell pages 1-3, ni2024clinicopathologicalfeaturesand pages 1-2, ishida2018aggressivenkcellleukemia pages 1-2, spaner2024casereportaggressive pages 1-2, hussein2020genomicandimmunophenotypic pages 2-3)

Direct abstract quotes (examples): - “Patients commonly present acutely with fever, constitutional symptoms, hepatosplenomegaly, and often disseminated intravascular coagulation or hemophagocytic syndrome.” (sumbly2022aggressivenaturalkiller pages 2-3) - “HLH can serve as the initial manifestation of ANKL.” (ni2024clinicopathologicalfeaturesand pages 1-2)

3.2 Age of onset, severity, progression

3.3 Frequency (where available)

  • HLH frequency: A 2024 pediatric-focused review notes HLH is common; in a separate case-literature preprint, HLH co-occurrence is described as frequent; quantitative, cohort-level HLH prevalence was not consistently extractable from all sources here. (ni2024clinicopathologicalfeaturesand pages 1-2)

3.4 Quality of life impact

Formal QoL instruments (EQ-5D/SF-36/PROMIS) were not identified in retrieved evidence. Clinical impact is inferred from fulminant symptoms, ICU-level complications (DIC, multiorgan failure), and extremely short survival. (hussein2020aggressivenkcell pages 1-3, tang2017aggressivenkcellleukemia pages 1-2)

3.5 Suggested HPO terms (non-exhaustive)

4. Genetic / molecular information

4.1 Causal genes

ANKL is not a monogenic germline disorder in the retrieved evidence. It is characterized by somatic alterations and pathway dysregulation.

4.2 Recurrently altered genes and pathways (with frequencies)

Multiple sources converge on three major molecular themes: JAK/STAT activation, epigenetic dysregulation, and TP53/DNA repair impairment, with additional contribution from RAS/MAPK signaling. (hussein2020aggressivenkcell pages 1-3, dufva2018aggressivenaturalkillercell pages 3-4)

JAK/STAT pathway

Visual evidence from Dufva et al. shows JAK-STAT component alterations and copy-number gains and summarizes frequencies across cohorts (including JAK2/STAT3/STAT5 alterations). (dufva2018aggressivenaturalkillercell media 01c6d37e, dufva2018aggressivenaturalkillercell media 2b03bded)

Epigenetic modifiers

TP53 pathway

DDX3X and RAS/MAPK

4.3 Epigenetics

ANKL epigenetic dysregulation is supported by recurrent mutations in epigenetic modifiers and literature noting methylation events (e.g., HACE1 hypermethylation mentioned in the large cohort background). (tang2017aggressivenkcellleukemia pages 1-2, hussein2020aggressivenkcell pages 1-3)

4.4 Chromosomal abnormalities

Clonal cytogenetic abnormalities are reported in clinical series (5/12 in one series). (hussein2020genomicandimmunophenotypic pages 1-2)

4.5 Mechanistic chain (pathophysiology synthesis)

A plausible causal chain supported by current evidence is: 1) EBV infection of NK lineage cells (EBER+) and/or host immune dysregulation contributes to transformation and/or inflammatory phenotype. (hussein2020genomicandimmunophenotypic pages 1-2, ishida2018aggressivenkcellleukemia pages 1-2) 2) Somatic alterations (JAK/STAT activation; epigenetic modifier and TP53 pathway lesions; RAS/MAPK) promote malignant proliferation, survival, and immune evasion. (dufva2018aggressivenaturalkillercell pages 3-4, tang2017aggressivenkcellleukemia pages 2-4) 3) NK-cell cytokine programs and pathway-driven transcriptional changes (including IL10–STAT3–MYC axis described in reviews) contribute to “cytokine storm” physiology and HLH-like systemic inflammation. (hussein2020genomicandimmunophenotypic pages 1-2, hussein2020aggressivenkcell pages 3-5) 4) Downstream manifestations include cytopenias, HLH, DIC, liver dysfunction, and multiorgan failure, driving high early mortality. (hussein2020aggressivenkcell pages 1-3, tang2017aggressivenkcellleukemia pages 1-2)

4.6 Suggested ontology terms

  • GO biological process (examples): JAK-STAT cascade (GO:0007259), cytokine-mediated signaling pathway (GO:0019221), regulation of apoptotic process (GO:0042981), leukocyte proliferation (GO:0070661)
  • Cell Ontology (CL) (examples): natural killer cell CL:0000623; malignant NK cell (no single CL term; represent as NK cell + neoplastic context)

5. Environmental information

Infectious agents

Other environmental and lifestyle associations were not identified in retrieved evidence.

6. Mechanism / pathophysiology

6.1 Molecular pathways (high-confidence)

6.2 Immune involvement

ANKL frequently presents with HLH and systemic inflammation; NK lineage biology (cytokine secretion programs) is implicated as a contributor to cytokine storm physiology in reviews. (hussein2020aggressivenkcell pages 3-5, spaner2024casereportaggressive pages 1-2)

6.3 Molecular profiling / multi-omics

  • Genomics: WES and targeted sequencing characterize recurrent pathways; Dufva et al. provides integrated genomics + drug sensitivity profiling highlighting pathway vulnerabilities. (dufva2018aggressivenaturalkillercell pages 3-4)

Not found in retrieved evidence: single-cell or spatial transcriptomics dedicated to ANKL.

7. Anatomical structures affected

7.1 Organ level

Commonly involved sites include bone marrow and peripheral blood, with frequent involvement of liver and spleen; lymph nodes may be involved; less commonly skin/soft tissue/lung are described in recent pediatric case review. (ni2024clinicopathologicalfeaturesand pages 1-2, ishida2018aggressivenkcellleukemia pages 1-2)

7.2 Tissue/cell level

7.3 Suggested UBERON terms (examples)

8. Temporal development

8.1 Onset pattern

Often acute with rapidly progressive systemic illness prompting “acute leukemia” evaluation. (hussein2020genomicandimmunophenotypic pages 2-3)

8.2 Progression

A large cohort distinguished: - Classic ANKL: fulminant presentation and very short OS. - Subacute ANKL subtype: prolonged prodromal IM-like phase >90 days (median 115 days) before fulminant onset, with survival advantage and differing TP53 mutation enrichment. (tang2017aggressivenkcellleukemia pages 2-4)

9. Inheritance and population

9.1 Epidemiology

Robust population incidence/prevalence rates were not found in the retrieved evidence (likely due to rarity and registry limitations). The largest cohort notes extreme rarity (hundreds of cases in the literature) and geographic predilection. (tang2017aggressivenkcellleukemia pages 1-2, hussein2020aggressivenkcell pages 1-3)

9.2 Demographics (quantitative)

9.3 Inheritance

No germline inheritance pattern is established in retrieved evidence; ANKL is characterized by somatic oncogenic alterations.

10. Diagnostics

10.1 Diagnostic approach (real-world)

ANKL diagnosis is challenging due to variable morphology and lack of a single defining marker; it requires integration of: - Peripheral blood and bone marrow morphology - Flow cytometry (NK immunophenotype) - EBV testing (EBER ISH) - IHC and NGS when feasible In a clinicopathologic series, the acute presentation triggered marrow sampling with suspicion of acute leukemia. (hussein2020genomicandimmunophenotypic pages 2-3)

10.2 Immunophenotype (high-yield diagnostic signature)

Across series and reviews, a core pattern includes: - Positive: CD56, CD94, CD2; cytotoxic markers (granzyme B, TIA-1, perforin); often EBER+ (EBV-associated subset) - Negative: surface CD3, CD4, CD5, CD57; TCRαβ/γδ - Bone marrow patterns: interstitial or intrasinusoidal/sinusoidal infiltration patterns. (hussein2020genomicandimmunophenotypic pages 1-2, hussein2020aggressivenkcell pages 3-5, hussein2020genomicandimmunophenotypic pages 2-3)

Quantitative immunophenotype from a 12-case series: CD56+ (12/12), CD94+ (9/9), CD2+ (10/12), EBER+ (9/12); surface CD3− (12/12), CD5− (11/11), CD57− (9/9), TCRαβ− (11/11), TCRγδ− (11/11). (hussein2020genomicandimmunophenotypic pages 1-2)

10.3 Differential diagnosis (examples)

10.4 Suggested tests / biomarkers

  • EBER ISH in marrow/tissue
  • Flow cytometry with NK markers (CD56, CD94, CD16, CD2; absence of surface CD3/TCR)
  • Plasma EBV DNA (used in related NK/T malignancies; specific ANKL thresholds not established in retrieved evidence)

11. Outcome / prognosis

11.1 Key statistics

11.2 Prognostic factors (reported)

Univariate/multivariate analyses in the large cohort identified clinical subtype, LDH, and treatment modality as prognostic; administration of L-asparaginase-based chemotherapy and allo-HSCT were associated with improved survival. (tang2017aggressivenkcellleukemia pages 2-4)

12. Treatment

12.1 Standard practice (current real-world implementation)

Evidence across cohorts/reviews supports: 1) L-asparaginase (or pegylated asparaginase)–containing induction chemotherapy (e.g., SMILE, AspaMetDex, related regimens) 2) Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in eligible responders Despite these strategies, outcomes remain poor for many patients due to rapid progression and treatment-related toxicity in critically ill presentations. (ni2024clinicopathologicalfeaturesand pages 1-2, tang2017aggressivenkcellleukemia pages 1-2, tang2017aggressivenkcellleukemia pages 2-4)

12.2 Chemotherapy outcomes (quantitative)

In Tang et al. (n=113 cohort), among 13 newly diagnosed patients treated with AspaMetDex chemotherapy alone: - CR: 30.77% (4/13) - ORR: 76.92% (10/13) - Median OS: 115 days (range 37–450) - Grade 3–4 hematologic AEs: 53.84% (7/13) These data highlight that responses are achievable, but durability is limited without consolidation. (tang2017aggressivenkcellleukemia pages 2-4)

A 2024 pediatric case review notes chemotherapy CR rates overall as <36% and summarizes that allo-HSCT still has high relapse/progression within 1 year (~55.5%). (ni2024clinicopathologicalfeaturesand pages 1-2)

12.3 Allo-HSCT outcomes (quantitative)

In Tang et al., 7 patients underwent allo-HSCT after CR: - Median OS: 300 days (range 174–1480) - 2-year OS: 42.86% (3/7) This supports allo-HSCT as a key consolidation strategy when remission is achieved and a donor is available. (tang2017aggressivenkcellleukemia pages 2-4)

12.4 Emerging/targeted therapies (expert analysis)

Genomic and drug profiling evidence indicates potential vulnerabilities: - JAK inhibition (for JAK/STAT-activated disease) - BCL2 inhibition (drug sensitivity profiling highlighted NK cells’ sensitivity) - Immune checkpoint blockade in selected contexts (PD-L1 expression reported in a subset) These approaches are not yet established as standard-of-care in the retrieved evidence but are rationally motivated by the genomic landscape. (hussein2020genomicandimmunophenotypic pages 1-2, dufva2018aggressivenaturalkillercell pages 3-4)

12.5 Clinical trials (NCT identifiers)

  • NCT03719105 (start 2019-03-01; Early Phase 1; Recruiting): Modified SMILE (mSMILE) including calaspargase pegol; pembrolizumab added for <CR after 2 cycles; followed by allo-HSCT when possible; explicitly includes ANKL in cohort 1. (NCT03719105 chunk 1)
  • URL: https://clinicaltrials.gov/study/NCT03719105
  • NCT03623087 (start 2017-07-01; Phase 3; status uncertain in record): “SIMPLE” chemotherapy regimen (cisplatin, gemcitabine, ifosfamide, etoposide, L-asparaginase, dexamethasone) designed as non-inferiority vs SMILE and includes aggressive NK leukaemia among target conditions. (NCT03623087 chunk 1)
  • URL: https://clinicaltrials.gov/study/NCT03623087
  • NCT05863234 (2023; Phase I/II; Recruiting; n=7): PPMX-T003 continuous IV administration safety/PK study in ANKL; excludes patients eligible for chemotherapy. (NCT05863234 chunk 1)
  • URL: https://clinicaltrials.gov/study/NCT05863234

12.6 Suggested MAXO terms (examples)

  • Chemotherapy MAXO:0000647
  • L-asparaginase therapy (map as chemotherapy + specific drug exposure; MAXO may not have a dedicated asparaginase term)
  • Allogeneic hematopoietic stem cell transplantation MAXO:0000747 (or closest HSCT term depending on MAXO release)
  • Immune checkpoint inhibitor therapy (immunotherapy; PD-1 inhibitor)

13. Prevention

No primary prevention strategies are established for ANKL in retrieved evidence. Prevention is largely not applicable beyond general EBV disease management and immunosuppression/immune dysregulation surveillance in high-risk contexts (not quantified here).

14. Other species / natural disease

No naturally occurring veterinary analogs were identified in retrieved evidence.

15. Model organisms

No dedicated animal models were identified in the retrieved evidence. The strongest mechanistic evidence here is from human tumor genomics and ex vivo drug sensitivity profiling. (dufva2018aggressivenaturalkillercell pages 3-4)

Recent developments & 2023–2024 highlights (prioritized)

1) 2024 case-based literature emphasizes that ANKL may present as refractory EBV-HLH and that lack of a “distinct immunologic and morphologic signature” delays diagnosis; early, repeated marrow/peripheral blood flow cytometry is highlighted as critical. (spaner2024casereportaggressive pages 1-2) 2) 2024 pediatric case series supports the operational treatment strategy of intensive pegaspargase/anthracycline-containing chemotherapy with consideration of HSCT, while underscoring high early mortality (e.g., tumor lysis) and the need for rapid supportive care. (ni2024clinicopathologicalfeaturesand pages 1-2) 3) WHO/ICC-era classification synthesis (2024) provides clinicians/pathologists a consolidated view of how modern frameworks align, improving standardization of terminology and diagnostic categorization for mature T/NK neoplasms. (ferry2024maturebt pages 8-10)

Key statistics (for knowledge base)

Visual evidence (genomic landscape)

Dufva et al. provide figure panels and a table summarizing JAK-STAT pathway alterations (mutations and copy-number gains) across ANKL cohorts and related NK/T malignancies; these visuals support the centrality of JAK/STAT dysregulation in ANKL and the rationale for pathway-directed therapy hypotheses. (dufva2018aggressivenaturalkillercell media 01c6d37e, dufva2018aggressivenaturalkillercell media 2b03bded)

Limitations of this evidence set

  • Several requested identifiers (MONDO, OMIM, Orphanet, MeSH, ICD-10/ICD-11) were not available from the retrieved texts in this run.
  • Many articles in this run do not provide PMIDs in the extracted text, so PMID-preferring citations cannot always be satisfied without additional PubMed-specific retrieval.
  • Incidence/prevalence rates and validated QoL measures were not found in the retrieved evidence.

References

  1. (hussein2020aggressivenkcell pages 1-3): Siba El Hussein, L. Medeiros, and Joseph Khoury. Aggressive nk cell leukemia: current state of the art. Cancers, 12:2900, Oct 2020. URL: https://doi.org/10.3390/cancers12102900, doi:10.3390/cancers12102900. This article has 67 citations.

  2. (spaner2024casereportaggressive pages 1-2): Caroline Spaner, Jessica Durkee-Shock, Andrew Weng, Ryan Stubbins, Alina S. Gerrie, Stefania Pittaluga, Jeffrey I. Cohen, and Luke Y. C. Chen. Case report: aggressive natural killer cell leukemia and refractory hemophagocytic lymphohistiocytosis in an adolescent. Frontiers in Hematology, Jul 2024. URL: https://doi.org/10.3389/frhem.2024.1413794, doi:10.3389/frhem.2024.1413794. This article has 0 citations.

  3. (ferry2024maturebt pages 8-10): Judith A. Ferry, Brian Hill, and Eric D. Hsi. Mature b, t and nk-cell, plasma cell and histiocytic/dendritic cell neoplasms: classification according to the world health organization and international consensus classification. Journal of Hematology & Oncology, Jul 2024. URL: https://doi.org/10.1186/s13045-024-01570-5, doi:10.1186/s13045-024-01570-5. This article has 19 citations and is from a domain leading peer-reviewed journal.

  4. (hussein2020genomicandimmunophenotypic pages 1-2): Siba El Hussein, Keyur P. Patel, Hong Fang, Beenu Thakral, Sanam Loghavi, Rashmi Kanagal-Shamanna, Sergej Konoplev, Elias J. Jabbour, L. Jeffrey Medeiros, and Joseph D. Khoury. Genomic and immunophenotypic landscape of aggressive nk-cell leukemia. The American Journal of Surgical Pathology, 44:1235-1243, Jun 2020. URL: https://doi.org/10.1097/pas.0000000000001518, doi:10.1097/pas.0000000000001518. This article has 46 citations.

  5. (ishida2018aggressivenkcellleukemia pages 1-2): Fumihiro Ishida. Aggressive nk-cell leukemia. Frontiers in Pediatrics, Oct 2018. URL: https://doi.org/10.3389/fped.2018.00292, doi:10.3389/fped.2018.00292. This article has 66 citations.

  6. (tang2017aggressivenkcellleukemia pages 1-2): Yuan Tang, D. Wang, H. Luo, M. Xiao, H-S Zhou, D. Liu, Shaoping Ling, N. Wang, X-L Hu, Y. Luo, X. Mao, Q. Ao, J. Huang, W. Zhang, L. Sheng, L. Zhu, Z. Shang, L. Gao, P-L Zhang, M. Zhou, K. Zhou, L. Qiu, Q.‐F. Liu, H.-Y. Zhang, J. Li, J. Jin, L. Fu, W-L Zhao, J-P Chen, X. Du, G. Huang, Q-f Wang, J. Zhou, and L. Huang. Aggressive nk-cell leukemia: clinical subtypes, molecular features, and treatment outcomes. Blood Cancer Journal, Dec 2017. URL: https://doi.org/10.1038/s41408-017-0021-z, doi:10.1038/s41408-017-0021-z. This article has 72 citations and is from a domain leading peer-reviewed journal.

  7. (hussein2020aggressivenkcell pages 3-5): Siba El Hussein, L. Medeiros, and Joseph Khoury. Aggressive nk cell leukemia: current state of the art. Cancers, 12:2900, Oct 2020. URL: https://doi.org/10.3390/cancers12102900, doi:10.3390/cancers12102900. This article has 67 citations.

  8. (ni2024clinicopathologicalfeaturesand pages 1-2): Yongan Ni, Lei Li, Yuping Wang, and Lirong Sun. Clinicopathological features and treatment of aggressive natural killer cell leukemia: case series and literature review. The Turkish journal of pediatrics, 66 4:481-489, Oct 2024. URL: https://doi.org/10.24953/turkjpediatr.2024.5072, doi:10.24953/turkjpediatr.2024.5072. This article has 1 citations.

  9. (hussein2020genomicandimmunophenotypic pages 2-3): Siba El Hussein, Keyur P. Patel, Hong Fang, Beenu Thakral, Sanam Loghavi, Rashmi Kanagal-Shamanna, Sergej Konoplev, Elias J. Jabbour, L. Jeffrey Medeiros, and Joseph D. Khoury. Genomic and immunophenotypic landscape of aggressive nk-cell leukemia. The American Journal of Surgical Pathology, 44:1235-1243, Jun 2020. URL: https://doi.org/10.1097/pas.0000000000001518, doi:10.1097/pas.0000000000001518. This article has 46 citations.

  10. (dufva2018aggressivenaturalkillercell pages 3-4): Olli Dufva, Matti Kankainen, Tiina Kelkka, Nodoka Sekiguchi, Shady Adnan Awad, Samuli Eldfors, Bhagwan Yadav, Heikki Kuusanmäki, Disha Malani, Emma I Andersson, Paavo Pietarinen, Leena Saikko, Panu E. Kovanen, Teija Ojala, Dean A. Lee, Thomas P. Loughran, Hideyuki Nakazawa, Junji Suzumiya, Ritsuro Suzuki, Young Hyeh Ko, Won Seog Kim, Shih-Sung Chuang, Tero Aittokallio, Wing C. Chan, Koichi Ohshima, Fumihiro Ishida, and Satu Mustjoki. Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight jak-stat signaling as therapeutic target. Nature Communications, Apr 2018. URL: https://doi.org/10.1038/s41467-018-03987-2, doi:10.1038/s41467-018-03987-2. This article has 163 citations and is from a highest quality peer-reviewed journal.

  11. (sumbly2022aggressivenaturalkiller pages 2-3): Vikram Sumbly, Mallorie Vest, and Ian Landry. Aggressive natural killer cell leukemia: a brief overview of its genomic landscape, histological features, and current management. Cureus, Feb 2022. URL: https://doi.org/10.7759/cureus.22537, doi:10.7759/cureus.22537. This article has 17 citations.

  12. (NCT03623087 chunk 1): Professor Yok-lam Kwong. SIMPLE Chemotherapy for NK Lymphoma/Leukaemia. The University of Hong Kong. 2017. ClinicalTrials.gov Identifier: NCT03623087

  13. (dufva2018aggressivenaturalkillercell media 01c6d37e): Olli Dufva, Matti Kankainen, Tiina Kelkka, Nodoka Sekiguchi, Shady Adnan Awad, Samuli Eldfors, Bhagwan Yadav, Heikki Kuusanmäki, Disha Malani, Emma I Andersson, Paavo Pietarinen, Leena Saikko, Panu E. Kovanen, Teija Ojala, Dean A. Lee, Thomas P. Loughran, Hideyuki Nakazawa, Junji Suzumiya, Ritsuro Suzuki, Young Hyeh Ko, Won Seog Kim, Shih-Sung Chuang, Tero Aittokallio, Wing C. Chan, Koichi Ohshima, Fumihiro Ishida, and Satu Mustjoki. Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight jak-stat signaling as therapeutic target. Nature Communications, Apr 2018. URL: https://doi.org/10.1038/s41467-018-03987-2, doi:10.1038/s41467-018-03987-2. This article has 163 citations and is from a highest quality peer-reviewed journal.

  14. (dufva2018aggressivenaturalkillercell media 2b03bded): Olli Dufva, Matti Kankainen, Tiina Kelkka, Nodoka Sekiguchi, Shady Adnan Awad, Samuli Eldfors, Bhagwan Yadav, Heikki Kuusanmäki, Disha Malani, Emma I Andersson, Paavo Pietarinen, Leena Saikko, Panu E. Kovanen, Teija Ojala, Dean A. Lee, Thomas P. Loughran, Hideyuki Nakazawa, Junji Suzumiya, Ritsuro Suzuki, Young Hyeh Ko, Won Seog Kim, Shih-Sung Chuang, Tero Aittokallio, Wing C. Chan, Koichi Ohshima, Fumihiro Ishida, and Satu Mustjoki. Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight jak-stat signaling as therapeutic target. Nature Communications, Apr 2018. URL: https://doi.org/10.1038/s41467-018-03987-2, doi:10.1038/s41467-018-03987-2. This article has 163 citations and is from a highest quality peer-reviewed journal.

  15. (tang2017aggressivenkcellleukemia pages 2-4): Yuan Tang, D. Wang, H. Luo, M. Xiao, H-S Zhou, D. Liu, Shaoping Ling, N. Wang, X-L Hu, Y. Luo, X. Mao, Q. Ao, J. Huang, W. Zhang, L. Sheng, L. Zhu, Z. Shang, L. Gao, P-L Zhang, M. Zhou, K. Zhou, L. Qiu, Q.‐F. Liu, H.-Y. Zhang, J. Li, J. Jin, L. Fu, W-L Zhao, J-P Chen, X. Du, G. Huang, Q-f Wang, J. Zhou, and L. Huang. Aggressive nk-cell leukemia: clinical subtypes, molecular features, and treatment outcomes. Blood Cancer Journal, Dec 2017. URL: https://doi.org/10.1038/s41408-017-0021-z, doi:10.1038/s41408-017-0021-z. This article has 72 citations and is from a domain leading peer-reviewed journal.

  16. (NCT03719105 chunk 1): Mitchell Cairo. Chemoimmunotherapy and Allogeneic Stem Cell Transplant for NK T-cell Leukemia/Lymphoma. New York Medical College. 2019. ClinicalTrials.gov Identifier: NCT03719105

  17. (NCT05863234 chunk 1): Safety Evaluation Study for Patients With Aggressive NK-cell Leukemia. Hiroshima University Hospital. 2023. ClinicalTrials.gov Identifier: NCT05863234