Azacitidine-induced remission enables allogeneic transplantation in TET2/BCOR-mutant relapsed extranodal natural killer/T-cell lymphoma: a case report

Extranodal NK/T-cell lymphoma (ENKTL) remains one of the most lethal lymphomas in the relapsed/refractory setting. Asparaginase-based chemotherapy and, more recently, immune checkpoint inhibitors have improved outcomes, but there is no established standard of care for patients who are refractory to both asparaginase-based regimens and PD-1/PD-L1 blockade.

Recent genomic studies have underscored the high prevalence of alterations affecting epigenetic regulators including TET2, BCOR, KMT2D, and ARID1A, highlighting epigenetic deregulation as a central feature of ENKTL pathogenesis and a potential therapeutic vulnerability. Although preclinical work has shown that hypomethylating agents (HMA) can restore silenced differentiation programs and induce tumor regression in ENKTL models,¹ clinical evidence supporting their use remains sparse. We report what appears to be the first case of relapsed ENKTL with co-occurring TET2 and BCOR mutations achieving a complete remission with azacitidine (AZA) monotherapy, enabling subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). A 47-year-old woman of Middle Eastern origin presented to Geneva University Hospitals (Geneva, Switzerland) with progressive, painless swelling of the upper eyelid and ptosis. Orbital magnetic resonance imaging (MRI) revealed left-sided enhancing extraconal masses. A biopsy confirmed Epstein-Barr virus (EBV)-positive ENKTL (CD56⁺, cytoplasmic CD3ε⁺, CD5^–, granzyme B⁺, TIA1⁺) (Figure 1A). Baseline [18F]-FDG positron emission tomography/computed tomography (PET/CT) showed disease confined to the orbits. Plasma EBV DNA was 9.4x10³ IU/mL, and both bone marrow and cerebrospinal fluid (CSF) analyses were negative. Her prognostic index of natural killer lymphoma-Epstein-Barr virus DNA (PINK-E) score was 2, indicating intermediate-risk disease.² The patient provided written general research consent. Ethics approval was not required for this anonymized single case report under the Swiss Human Research Act (HRA).

The patient received four cycles of SMILE chemotherapy: intravenous (IV) methotrexate (2 g/m² on day 1), ifosfamide (1.5 g/m²/day IV on days 2-4), etoposide (100 mg/m²/day IV on days 2-4), dexamethasone (40 mg/day on days 2-4), and L-asparaginase (6,000 IU/m²/day IV on days 8-17). This was followed by radiotherapy, and a complete metabolic response was achieved with EBV clearance (Figure 1B). Fourteen months later, she relapsed with an orbital recurrence. Salvage therapy with pembrolizumab combined with two cycles of GELOX (IV gemcitabine [1,000 mg/m² on days 1 and 8], oxaliplatin [130 mg/m² IV on day 1], and L-asparaginase [6,000 IU/m²/day IV on days 1-7]) was administered, followed by radiotherapy with concurrent pembrolizumab and cisplatin. Despite these treatments, the disease progressed with leptomeningeal dissemination and bone marrow involvement. High-dose cytarabine with pembrolizumab, additional radiotherapy, and intrathecal cytarabine plus methotrexate produced only transient normalization of CSF parameters without neurological improvement (Figure 1B).

Targeted next-generation sequencing of diagnostic biopsies using a limited 27-gene panel identified pathogenic mutations in epigenetic regulators, including a clonal TET2 missense variant (c.5704T>A, p.Tyr1902Asn) affecting the dioxygenase catalytic domain and a splice-site BCOR mutation (c.4071+1G>A). Subsequent analysis of the relapse sample using a broader 400-gene panel confirmed the persistence of the TET2 variant and identified a truncating BCOR mutation (c.1570dup; p.Ser524LysfsTer33), whereas the initial splice-site BCOR variant was no longer detected, consistent with clonal heterogeneity during disease progression (Table 1). Together, these alterations are expected to impair 5-methylcytosine oxidation and disrupt PRC1.1-mediated repression, respectively, leading to marked epigenetic dysregulation.³

Given the co-occurrence of TET2 and BCOR mutations and reports of AZA responsiveness in TET2-mutant T-cell lymphomas,⁴ off-label AZA was initiated at 75 mg/m² sub-cutaneously on days 1-7 of a 28-day cycle, together with weekly intrathecal cytarabine. Treatment was well tolerated, with grade 2 fatigue, mild injection-site erythema, and one episode of transient grade 3 neutropenia. Following a single cycle, plasma EBV DNA became undetectable, neurological symptoms resolved, CSF cleared, and PET/ CT at day 28 showed a complete metabolic remission (Figure 1C). This therapeutic response was confirmed by the absence of detectable NK/T cells in the bone marrow. Notably, no somatic variants were detected in this sample, arguing against the presence of a dominant ancestral clonal hematopoiesis of indeterminate potential (CHIP) clone in this patient within the analytical sensitivity of the assay. A second AZA cycle was given as bridging therapy before myeloablative conditioning (fludarabine 120 mg/m² and total body irradiation 10 Gy) and allo-HSCT from an HLA-matched sibling.

The post-transplant course was complicated by grade 2 acute graft-versus-host disease of the skin and gastrointestinal tract, controlled with prednisone and later ruxolitinib. EBV viremia reappeared on day +70, followed by systemic relapse on day +133. Reintroduction of AZA was ineffective in the context of massive marrow infiltration and secondary hemophagocytic lymphohistiocytosis, and the patient died on day +160. Notably, we observed the persistence of TET2 and BCOR mutations at lower allele frequencies (approx. 4%) in the post-transplant relapse biopsy, together with the emergence of additional low-frequency mutations in CSF3R and DNMT3A, consistent with post-transplant clonal evolution that may have contributed to the lack of response to re-exposure to AZA. Nonetheless, AZA had produced a deep and rapid remission that created a window for potentially curative allo-HSCT.

Figure 1.Azacitidine induces complete remission in relapsed TET2- and BCOR-mutant natural killer/T-cell lymphoma. (A) Histopathological examination of the orbital biopsy showing dense infiltrates of atypical lymphoid cells with angiocentric growth and necrosis (Hematoxylin&Eosin, H&E). Tumor cells expressed CD3, CD8, CD56, and granzyme B (GrB), lacked CD5, and showed a high proliferative index by MIB1 staining. Epstein-Barr virus (EBV)-encoded RNA (EBER) in situ hybridization confirmed EBV positivity. Scale bars, 50 µm. (B) Clinical course showing treatment timeline, plasma EBV DNA (blue line), and corresponding therapeutic interventions. AZA: azacitidine (75 mg/m² subcutaneously on days 1-7); CNS: central nervous system; CR: complete remission; CSF: cerebrospinal fluid; GELOX: intravenous (IV) gemcitabine (1,000 mg/m² on days 1 and 8), oxaliplatin (130 mg/m² IV on day 1), and L-asparaginase (6,000 IU/m²/day IV on days 1-7); HDAC: high-dose cytarabine (6 g/m² on days 1, 3 and 5); alloHSCT: allogeneic hematopoietic stem cell transplantation; IT: intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and methylprednisolone 15 mg); Pembro: pembrolizumab; Rel: relapse; RxT: radiotherapy; SMILE: methotrexate (2 g/m² IV on day 1), ifosfamide (1.5 g/m²/day IV on days 2-4), etoposide (100 mg/m²/day IV on days 2-4), dexamethasone (40 mg/day on days 2-4), and L-asparaginase (6,000 IU/m²/day IV on days 8-17). (C) Maximum intensity projection [¹⁸F]-FDG positron emission tomography/computed tomography (PET/CT) images: baseline pre-AZA PET/CT demonstrated intensely FDG-avid infiltration of the left premaxillary fat, accompanied by multiple FDG-avid lymphadenopathies involving the cervical, mediastino-hilar, mesenteric, and cardiophrenic regions as well as bilateral pulmonary FDG-avid foci, consistent with disease recurrence and progression. Following a single cycle of AZA therapy, the subsequent PET/CT demonstrated complete metabolic remission of all peri-orbital and systemic lesions.

Table 1.Somatic variant summary across disease course.

Therapeutic options for relapsed or refractory ENKTL remain limited. allo-HSCT offers the only possibility of durable remission but relies on achieving disease control beforehand. PD-1 blockade yields responses in approximately 40% of patients, aided by frequent CD274 (PD-L1) 3’UTR alterations, yet durable control is rare.⁵ In contrast, clinical experience with HMA in ENKTL is extremely limited. To our knowledge, only one complete remission has been reported; this was in a patient treated with oral AZA and romidepsin in a phase I study.⁶ In this setting, the complete remission achieved with AZA monotherapy after multiple prior lines of therapy in our patient is notable.

Co-occurring TET2 and BCOR mutations in our case may have contributed to a permissive epigenetic context for HMA activity, consistent with observations in other T-cell and myeloid malignancies harboring epigenetic lesions.⁴ Yet epigenetic vulnerability in ENKTL likely extends beyond these specific alterations. Genomic studies show that ENKTL cases frequently carry mutations in chromatin modifiers or DNA methylation regulators. Xiong et al. reported that two-thirds of TET2-mutant tumors harbor additional epigenetic hits, including BCOR and KMT2D,⁷ findings echoed by Oishi et al.⁸ and by recent profiling studies highlighting recurrent epigenetic drivers on the X chromosome.⁹ Notably, this concept has been further supported by a recent clinical study showing that DNMT inhibitors can overcome PD-1 resistance in relapsed/refractory ENKTL through epigenetic reprogramming and immune pathway restoration.¹⁰ However, the phase III ORACLE trial comparing oral AZA with investigator’s-choice standard therapy in relapsed/ refractory TFH lymphoma did not meet its primary endpoint of improved progression-free survival and did not show a preferential benefit in patients harboring TET2 or other epigenetic mutations, indicating that HMA activity is not restricted to specific epigenetic genotypes.¹¹ In addition, clinical reports have described responses to HMA in the absence of TET2 mutations in angioimmunoblastic T-cell lymphoma, and functional screens in T-cell lymphoma models have not identified loss of TET2 or BCOR as being necessary for HMA sensitivity.^12,13 AZA can, therefore, be considered in selected relapsed/refractory ENKTL patients irrespective of TET2/BCOR status, particularly when standard options are exhausted.

Several biological features may account for the pronounced AZA sensitivity. Although co-occurring loss-of-function mutations in TET2 and BCOR may have contributed to HMA sensitivity, our observation does not prove a purely tumor-intrinsic, AZA-only effect. AZA can enhance tumor immunogenicity through viral mimicry and interferon pathway activation,^14,15 and persistent PD-1 receptor occupancy following prior pembrolizumab exposure may have further amplified this immune response, even if the delay between the last dose of pembrolizumab and the first administration of AZA was 3.8 months. This anti-tumor immune response may also have contributed to the neurological improvement despite limited CSF penetration of AZA. The combination of these mechanisms provides a coherent explanation for the rapid and profound remission observed after a single treatment cycle.

This case illustrates that AZA monotherapy can induce complete remission in relapsed ENKTL with epigenetic alterations, enabling subsequent allo-HSCT. These observations support further evaluation of HMA-based strategies in relapsed ENKTL, with integrated molecular profiling to better define the biological contexts associated with response.

Footnotes

• Received December 9, 2025
• Accepted March 26, 2026

Correspondence

J. TAMBURINI - jerome.tamburinibonnefoy@unige.ch

Disclosures

No conflicts of interest to disclose.

Contributions

Acknowledgments

We thank the patient for providing general consent allowing the use of her clinical data for research and publication. We thank the Division of Nuclear Medicine and Molecular Imaging and the Division of Clinical Pathology at Geneva University Hospitals, the Institut Ophtalmologique Jules-Gonin (Fondation Asile des Aveugles, Lausanne) as well as the Institute of Pathology Lausanne University Hospital for their role in patient’s care. We thank Professor Minerva Becker (Radiology Department, Geneva University Hospitals, Geneva, Switzerland) for expertise on central nervous system imaging.