RARE DISEASE
Extranodal nasal NK/T cell lymphoma
Extranodal nasal NK/T cell lymphoma
Extranodal nasal NK/T cell lymphoma
Synonyms: Angiocentric T-cell lymphoma, Lethal midline granuloma, NK/T-cell lymphoma, NKTCL, Nasal T/natural killer-cell lymphoma
Synonyms: Angiocentric T-cell lymphoma, Lethal midline granuloma, NK/T-cell lymphoma, NKTCL, Nasal T/natural killer-cell lymphoma
Synonyms: Angiocentric T-cell lymphoma, Lethal midline granuloma, NK/T-cell lymphoma, NKTCL, Nasal T/natural killer-cell lymphoma
Drug discovery
4
drugs
With orphan designations
Overview
Extranodal nasal NK/T-cell lymphoma (ENKTL) is an aggressive Epstein-Barr virus-associated non-Hodgkin lymphoma, primarily involving the nasal cavity and upper aerodigestive tract. Characterized by necrotic midline lesions, it shows geographic predominance in Asia and Latin America. Diagnosis relies on histopathology, EBV in situ hybridization, and cytotoxic markers (e.g., CD56+, granzyme B). Resistance to CHOP chemotherapy necessitates tailored approaches, combining radiotherapy and asparaginase-based regimens for optimal outcomes [1][6][10].
Therapies
Early-stage: Concurrent/sequential chemoradiotherapy (e.g., DeVIC + 50 Gy RT) with 5-year survival >80% [8][13][14].
Advanced-stage: Asparaginase-based regimens (SMILE, DDGP) ± PD-1 inhibitors (pembrolizumab); 2-year survival ~40% [3][8][18].
Avoid anthracyclines; RT remains critical even for chemotherapy-responsive disease [5][13][19].
Categories: rare hematological diseases, rare neoplastic diseases, rare skin diseases, rare transplant-related disorders
Research Papers
1,238 drug discovery papers about Extranodal nasal NK/T cell lymphoma, with 4 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,238 drug discovery papers about Extranodal nasal NK/T cell lymphoma, with 4 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-12 | ZBED6-driven nucleotide metabolic reprogramming improves sensitivity to anti-PD1 therapy in NK/T cell lymphoma.
NK/T-cell lymphoma (NKTL) is a highly aggressive non-Hodgkin's lymphoma characterized by extranodal involvement. Programmed cell death protein 1 (PD-1) monoclonal antibody (anti-PD1) treatment is ineffective in some patients, leading to recurrence or metastasis. The resistance to anti-PD1 treatment remains a major challenge in clinics. To identify the core molecules responsible for anti-PD1 treatment resistance and explore the possible molecular mechanisms behind it, simulating the human immune microenvironment during PD-1 treatment is essential. In this study, human peripheral blood mononuclear cells (PBMCs) were transplanted into immunodeficient mice to reconstitute human immunity in mice. The results showed that after immune reconstitution, human immune cells, especially T cells, remain at a high level (≥90%) for at least 4 weeks, indicating that human PBMCs were successfully reconstituted in immunodeficient mice. Two weeks after PBMCs implantation, human NKTL cells (SNK1, KHYG1 and YT) were subcutaneously inoculated into the right lower abdomen of mice. Then, high-dose anti-PD1 treatment was initiated (about 50 mm3, Sintilimab, twice a week, 10 mg/kg each time). The tumor from the mice was removed (≤than 1500 mm3) to prepare a single-cell suspension and re-implanted into the mice. The above process was repeated 5 times (280 days in total). The tumor growth inhibition (TGI) values of NKTL cells before and after induction (71.89% and 1.08% for KHYG1 cells, 54.37% and 3.79% for SNK1 cells, 51.17% and 6.34% for YT cells, respectively) confirmed the successful construction of anti-hPD1-induced resistance NKTL cells (SNK1-Re, KHYG1-Re and YT-Re). Subsequently, we performed transcriptomic, proteomic, and metabolomic analyses on the above resistant and sensitive cell lines. Through multiple functional experiments and clinical sample verification, we confirmed that the transcriptional repressor Zinc finger BED-type containing 6 (ZBED6) was a key biomarker for anti-PD1 treatment resistance in NKTL. Downregulated ZBED6 creates a thymidine-deficient environment by E2F transcription factor 1 (E2F1)-ribonucleoside-diphosphate reductase subunit M2 (RRM2)/dihydropyrimidine dehydrogenase (DPYD), in which drug-resistant tumor cells scavenge thymidine (TdR) from the tumor microenvironment via solute carrier family 29 member 1 (SLC29A1) to increase nucleotide synthesis, thereby establishing an immunosuppressive niche, resulting in the ineffectiveness of anti-PD1 immunotherapy.
2026-08-09 | Real-world outcomes of T cell lymphoma in a tertiary cancer center in Saudi Arabia.
T-cell and natural-killer (T/NK)-cell lymphomas are rare and aggressive malignancies. Prior to our study, no dedicated institutional survival analyses of T/NK-cell lymphomas had been published from Saudi Arabia. To evaluate the clinical characteristics, prognostic factors, and survival outcomes of patients with T/NK-cell lymphoma treated at a tertiary cancer referral centre in Saudi Arabia. Retrospective cohort study. King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia; January 2016 to December 2022. We reviewed medical records of 89 adults with histologically confirmed T/NK-cell lymphomas, including precursor and mature subtypes. Overall survival (OS) was estimated using the Kaplan-Meier method. Prognostic factors were assessed with univariate and multivariable Cox proportional hazards regression. To maintain a robust events-per-variable ratio, the multivariable model was restricted to four predictors. Five-year overall survival and identification of variables associated with mortality. 89 patients. The mean age was 49.5±20.5 years, and 62 patients (70%) were male. The most common subtypes were ALK-negative anaplastic large-cell lymphoma (n=20, 22%) and peripheral T-cell lymphoma, not otherwise specified (n=15, 17%). For the entire cohort (N=89), the 5-year OS was 56% (95% CI, 44%-67%); the Kaplan-Meier estimated mean OS over the full available follow-up was 116.4 months. In multivariable analysis restricted to 70 patients with complete data (26 deaths), elevated lactate dehydrogenase (LDH) (hazard ratio [HR]=7.66; 95% confidence interval [CI], 1.77-33.19; P=.006), Eastern Cooperative Oncology Group (ECOG) performance status >2 (HR=4.26; 95% CI, 1.60-11.33; P=.004), and renal insufficiency (HR=3.06; 95% CI, 1.34-6.97; P=.008) were independent predictors of worse survival. Anemia trended toward worse survival but did not reach independent significance (HR=2.30; 95% CI, 0.95-5.58; P=.066). Elevated LDH, poor performance status, and renal insufficiency are strong independent predictors of inferior survival. Stem cell transplantation did not demonstrate a survival benefit in this cohort. These findings underscore the importance of baseline laboratory and clinical variables for risk stratification and provide groundwork for multicentre studies and therapeutic optimisation in Saudi Arabia. Sample size and single-centre retrospective design limit generalisability. Transplant-specific details in treatment regimens were not evaluated.
2026-08-05 | Extranodal NK/T-cell lymphoma, nasal type, presenting as a necrotic palatal ulcer.
Extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, is an aggressive Epstein-Barr virus (EBV)-associated lymphoma that predominantly involves the nasal cavity and upper aerodigestive tract. Primary oral manifestations are rare and may clinically mimic benign inflammatory or infectious conditions, resulting in delayed diagnosis. This report presents a rare case of ENKTL initially manifesting as a rapidly progressive necrotizing palatal ulcer. A 44-year-old man presented with a three-week history of a necrotic ulcer on the posterior hard palate. Imaging revealed extensive midfacial destruction, including palatal perforation, nasal septal erosion, turbinate destruction, ethmoidal involvement, and medial orbital wall extension. Histopathologic examination demonstrated atypical large lymphoid cells with extensive necrosis and infiltration into adipose and muscle tissue. Immunohistochemical staining demonstrated diffuse expression of LCA and CD3, focal expression of CD30, absence of CD20, ALK, and CD56 expression, and a high proliferative activity, as evidenced by a Ki-67 index of approximately 90%. Based on the histomorphologic and immunophenotypic features, extranodal NK/T-cell lymphoma was suspected. Chromogenic in situ hybridization (CISH) for Epstein-Barr virus-encoded RNA (EBER) demonstrated strong nuclear positivity in atypical lymphoid cells, confirming the diagnosis of ENKTL, nasal type. The patient achieved complete remission after chemotherapy; however, eight months later, the patient developed a systemic relapse that was diagnosed as peripheral T-cell lymphoma. This case highlights the diagnostic complexity of ENKTL presenting as a destructive palatal lesion. Comprehensive histopathologic evaluation, detailed immunophenotyping, and EBV confirmation by EBER are essential for accurate diagnosis and timely oncologic management. ENKTL should be considered in the differential diagnosis of rapidly progressive oral necrotic lesions unresponsive to conventional therapy.
2026-08-03 | [Recent advances and future perspectives in the treatment of NK/T-cell lymphoma].
Extranodal natural killer/T-cell lymphoma (ENKL) is a rare lymphoid malignancy that has historically poor outcomes when treated with conventional lymphoma chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). In the early 2000s, treatment strategies designed to overcome multidrug resistance were adopted. The RT-2/3DeVIC (radiotherapy, dexamethasone, etoposide, ifosfamide, carboplatin) for newly diagnosed localized ENKL and SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) chemotherapy for newly diagnosed advanced-stage or relapsed/refractory ENKL, developed through clinical trials, subsequently improved the prognosis of patients with ENKL in real-world clinical practice in Japan. However, two outcome studies have also highlighted the limitations of these approaches. More recently, therapeutic development for ENKL has shifted toward PD-1/PD-L1 inhibitor-based strategies, as well as molecularly targeted therapies informed by advances in basic research. This review summarizes the current treatment landscape for ENKL in Japan, describes therapeutic developments outside Japan and ongoing investigational approaches, and discusses future directions in ENKL treatment development.
2026-07-27 | Real-World Outcomes of Frontline Multimodal Treatment Strategies for Localized Extranodal NK/T-Cell Lymphoma, Nasal Type: A Single-Center Vietnamese Cohort Study.
Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL-NT), is a rare and aggressive lymphoma for which real-world data from resource-limited settings remain scarce. This study evaluated the efficacy and safety of frontline multimodal treatment strategies for localized ENKTL-NT. We retrospectively analyzed 62 patients with localized ENKTL-NT treated at the Vietnam National Cancer Hospital between May 2019 and June 2025. Patients received concurrent chemoradiotherapy followed by VIPD or VIDL, or sequential chemoradiotherapy with GELOX/PGEMOX. Treatment responses, survival outcomes, and toxicities were assessed. The median age was 44 years, and 67.7% of patients had stage I disease. Baseline EBV-DNA positivity was detected in 46.8%, while 54.8% had PINKE scores of 1-2. The overall response rate was 93.5%, including an 85.5% complete response rate. Grade 3-4 neutropenia was the most common adverse event (18.7%). The estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 76.3% and 79.5%, respectively. Multivariable Cox analysis identified PINKE risk stratification as an independent predictor of both PFS and OS. Frontline multimodal treatment strategies achieved high response rates, favorable survival outcomes, and manageable toxicities in localized ENKTL-NT. The PINKE score remained an important prognostic factor, supporting risk-adapted treatment selection in routine clinical practice.
2026-08-12 | ZBED6-driven nucleotide metabolic reprogramming improves sensitivity to anti-PD1 therapy in NK/T cell lymphoma.
NK/T-cell lymphoma (NKTL) is a highly aggressive non-Hodgkin's lymphoma characterized by extranodal involvement. Programmed cell death protein 1 (PD-1) monoclonal antibody (anti-PD1) treatment is ineffective in some patients, leading to recurrence or metastasis. The resistance to anti-PD1 treatment remains a major challenge in clinics. To identify the core molecules responsible for anti-PD1 treatment resistance and explore the possible molecular mechanisms behind it, simulating the human immune microenvironment during PD-1 treatment is essential. In this study, human peripheral blood mononuclear cells (PBMCs) were transplanted into immunodeficient mice to reconstitute human immunity in mice. The results showed that after immune reconstitution, human immune cells, especially T cells, remain at a high level (≥90%) for at least 4 weeks, indicating that human PBMCs were successfully reconstituted in immunodeficient mice. Two weeks after PBMCs implantation, human NKTL cells (SNK1, KHYG1 and YT) were subcutaneously inoculated into the right lower abdomen of mice. Then, high-dose anti-PD1 treatment was initiated (about 50 mm3, Sintilimab, twice a week, 10 mg/kg each time). The tumor from the mice was removed (≤than 1500 mm3) to prepare a single-cell suspension and re-implanted into the mice. The above process was repeated 5 times (280 days in total). The tumor growth inhibition (TGI) values of NKTL cells before and after induction (71.89% and 1.08% for KHYG1 cells, 54.37% and 3.79% for SNK1 cells, 51.17% and 6.34% for YT cells, respectively) confirmed the successful construction of anti-hPD1-induced resistance NKTL cells (SNK1-Re, KHYG1-Re and YT-Re). Subsequently, we performed transcriptomic, proteomic, and metabolomic analyses on the above resistant and sensitive cell lines. Through multiple functional experiments and clinical sample verification, we confirmed that the transcriptional repressor Zinc finger BED-type containing 6 (ZBED6) was a key biomarker for anti-PD1 treatment resistance in NKTL. Downregulated ZBED6 creates a thymidine-deficient environment by E2F transcription factor 1 (E2F1)-ribonucleoside-diphosphate reductase subunit M2 (RRM2)/dihydropyrimidine dehydrogenase (DPYD), in which drug-resistant tumor cells scavenge thymidine (TdR) from the tumor microenvironment via solute carrier family 29 member 1 (SLC29A1) to increase nucleotide synthesis, thereby establishing an immunosuppressive niche, resulting in the ineffectiveness of anti-PD1 immunotherapy.
2026-08-09 | Real-world outcomes of T cell lymphoma in a tertiary cancer center in Saudi Arabia.
T-cell and natural-killer (T/NK)-cell lymphomas are rare and aggressive malignancies. Prior to our study, no dedicated institutional survival analyses of T/NK-cell lymphomas had been published from Saudi Arabia. To evaluate the clinical characteristics, prognostic factors, and survival outcomes of patients with T/NK-cell lymphoma treated at a tertiary cancer referral centre in Saudi Arabia. Retrospective cohort study. King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia; January 2016 to December 2022. We reviewed medical records of 89 adults with histologically confirmed T/NK-cell lymphomas, including precursor and mature subtypes. Overall survival (OS) was estimated using the Kaplan-Meier method. Prognostic factors were assessed with univariate and multivariable Cox proportional hazards regression. To maintain a robust events-per-variable ratio, the multivariable model was restricted to four predictors. Five-year overall survival and identification of variables associated with mortality. 89 patients. The mean age was 49.5±20.5 years, and 62 patients (70%) were male. The most common subtypes were ALK-negative anaplastic large-cell lymphoma (n=20, 22%) and peripheral T-cell lymphoma, not otherwise specified (n=15, 17%). For the entire cohort (N=89), the 5-year OS was 56% (95% CI, 44%-67%); the Kaplan-Meier estimated mean OS over the full available follow-up was 116.4 months. In multivariable analysis restricted to 70 patients with complete data (26 deaths), elevated lactate dehydrogenase (LDH) (hazard ratio [HR]=7.66; 95% confidence interval [CI], 1.77-33.19; P=.006), Eastern Cooperative Oncology Group (ECOG) performance status >2 (HR=4.26; 95% CI, 1.60-11.33; P=.004), and renal insufficiency (HR=3.06; 95% CI, 1.34-6.97; P=.008) were independent predictors of worse survival. Anemia trended toward worse survival but did not reach independent significance (HR=2.30; 95% CI, 0.95-5.58; P=.066). Elevated LDH, poor performance status, and renal insufficiency are strong independent predictors of inferior survival. Stem cell transplantation did not demonstrate a survival benefit in this cohort. These findings underscore the importance of baseline laboratory and clinical variables for risk stratification and provide groundwork for multicentre studies and therapeutic optimisation in Saudi Arabia. Sample size and single-centre retrospective design limit generalisability. Transplant-specific details in treatment regimens were not evaluated.
2026-08-05 | Extranodal NK/T-cell lymphoma, nasal type, presenting as a necrotic palatal ulcer.
Extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, is an aggressive Epstein-Barr virus (EBV)-associated lymphoma that predominantly involves the nasal cavity and upper aerodigestive tract. Primary oral manifestations are rare and may clinically mimic benign inflammatory or infectious conditions, resulting in delayed diagnosis. This report presents a rare case of ENKTL initially manifesting as a rapidly progressive necrotizing palatal ulcer. A 44-year-old man presented with a three-week history of a necrotic ulcer on the posterior hard palate. Imaging revealed extensive midfacial destruction, including palatal perforation, nasal septal erosion, turbinate destruction, ethmoidal involvement, and medial orbital wall extension. Histopathologic examination demonstrated atypical large lymphoid cells with extensive necrosis and infiltration into adipose and muscle tissue. Immunohistochemical staining demonstrated diffuse expression of LCA and CD3, focal expression of CD30, absence of CD20, ALK, and CD56 expression, and a high proliferative activity, as evidenced by a Ki-67 index of approximately 90%. Based on the histomorphologic and immunophenotypic features, extranodal NK/T-cell lymphoma was suspected. Chromogenic in situ hybridization (CISH) for Epstein-Barr virus-encoded RNA (EBER) demonstrated strong nuclear positivity in atypical lymphoid cells, confirming the diagnosis of ENKTL, nasal type. The patient achieved complete remission after chemotherapy; however, eight months later, the patient developed a systemic relapse that was diagnosed as peripheral T-cell lymphoma. This case highlights the diagnostic complexity of ENKTL presenting as a destructive palatal lesion. Comprehensive histopathologic evaluation, detailed immunophenotyping, and EBV confirmation by EBER are essential for accurate diagnosis and timely oncologic management. ENKTL should be considered in the differential diagnosis of rapidly progressive oral necrotic lesions unresponsive to conventional therapy.
2026-08-03 | [Recent advances and future perspectives in the treatment of NK/T-cell lymphoma].
Extranodal natural killer/T-cell lymphoma (ENKL) is a rare lymphoid malignancy that has historically poor outcomes when treated with conventional lymphoma chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). In the early 2000s, treatment strategies designed to overcome multidrug resistance were adopted. The RT-2/3DeVIC (radiotherapy, dexamethasone, etoposide, ifosfamide, carboplatin) for newly diagnosed localized ENKL and SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) chemotherapy for newly diagnosed advanced-stage or relapsed/refractory ENKL, developed through clinical trials, subsequently improved the prognosis of patients with ENKL in real-world clinical practice in Japan. However, two outcome studies have also highlighted the limitations of these approaches. More recently, therapeutic development for ENKL has shifted toward PD-1/PD-L1 inhibitor-based strategies, as well as molecularly targeted therapies informed by advances in basic research. This review summarizes the current treatment landscape for ENKL in Japan, describes therapeutic developments outside Japan and ongoing investigational approaches, and discusses future directions in ENKL treatment development.
2026-07-27 | Real-World Outcomes of Frontline Multimodal Treatment Strategies for Localized Extranodal NK/T-Cell Lymphoma, Nasal Type: A Single-Center Vietnamese Cohort Study.
Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL-NT), is a rare and aggressive lymphoma for which real-world data from resource-limited settings remain scarce. This study evaluated the efficacy and safety of frontline multimodal treatment strategies for localized ENKTL-NT. We retrospectively analyzed 62 patients with localized ENKTL-NT treated at the Vietnam National Cancer Hospital between May 2019 and June 2025. Patients received concurrent chemoradiotherapy followed by VIPD or VIDL, or sequential chemoradiotherapy with GELOX/PGEMOX. Treatment responses, survival outcomes, and toxicities were assessed. The median age was 44 years, and 67.7% of patients had stage I disease. Baseline EBV-DNA positivity was detected in 46.8%, while 54.8% had PINKE scores of 1-2. The overall response rate was 93.5%, including an 85.5% complete response rate. Grade 3-4 neutropenia was the most common adverse event (18.7%). The estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 76.3% and 79.5%, respectively. Multivariable Cox analysis identified PINKE risk stratification as an independent predictor of both PFS and OS. Frontline multimodal treatment strategies achieved high response rates, favorable survival outcomes, and manageable toxicities in localized ENKTL-NT. The PINKE score remained an important prognostic factor, supporting risk-adapted treatment selection in routine clinical practice.
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Drug Discovery Landscape
4 orphan drug designations for Extranodal nasal NK/T cell lymphoma.
4 orphan drug designations for Extranodal nasal NK/T cell lymphoma.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
EBV-induced natural T cell [EBViNT Cell] | cell therapies | FDA | 2022-09-27 | — | Eutilex Co. Ltd |
brentuximab vedotin | antibodies | FDA | 2018-11-13 | — | Seattle Genetics, Inc. |
Baltaleucel [CMD-003] | cell therapies | EMA | 2016-07-14 | — | Scendea (NL) B.V. |
Darinaparsin | small molecules | EMA | 2011-04-15 | — | IDEA Innovative Drug European Associates (Ireland) Limited |
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