Extranodal NK/T-cell lymphoma (ENKTCL) is a rare, highly aggressive lymphoid malignancy closely associated with Epstein–Barr virus (EBV) infection. Patients with advanced-stage or relapsed/refractory (R/R) disease continue to face poor outcomes, making effective treatment a longstanding clinical challenge. Recently, Director Zhihui Li and colleagues from Beijing GoBroad Boren Hospital published a study in Blood Advances entitled "HSCT May Improve Survival in Advanced Extranodal NK/T-Cell Lymphoma: A Single-Center Retrospective Study."The study demonstrated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) can improve survival in selected patients with high-risk, advanced R/R ENKTCL while providing important insights into precision risk stratification and individualized treatment strategies. Oncology Frontier – Hematology Frontier invited Director Zhihui Li to discuss the study’s key findings and their implications for future clinical practice.
Oncology Frontier – Hematology Frontier: Your recent study, “HSCT May Improve Survival in Advanced Extranodal NK/T-Cell Lymphoma: A Single-Center Retrospective Study,” was published in Blood Advances. To begin, could you describe the current treatment landscape for extranodal NK/T-cell lymphoma (ENKTCL) and the major challenges that remain?
Director Zhihui Li:
ENKTCL has evolved from being regarded as a nearly fatal disease to one managed through comprehensive treatment guided by precision risk stratification.
The incidence of ENKTCL is substantially higher in Asia, including China, and in Latin America than in Western countries. For patients with stage I–II disease, who account for approximately 70%–90% of cases, combined chemotherapy and radiotherapy remains the standard treatment and achieves cure rates exceeding 80%. However, outcomes remain poor for patients with stage III–IV disease or relapsed/refractory (R/R) ENKTCL, whose five-year overall survival (OS) is only about 40%.
Non-anthracycline chemotherapy based on pegaspargase remains a commonly used regimen. Unfortunately, once patients develop resistance or experience relapse, treatment options become extremely limited.
Several major challenges continue to hinder ENKTCL management.
The first is diagnostic complexity.
ENKTCL encompasses a broad pathological spectrum and lacks highly specific immunophenotypic markers, making it difficult to distinguish from other EBV-positive lymphoproliferative disorders. Early symptoms, such as nasal obstruction or facial swelling, are also frequently mistaken for infection or inflammatory disease, delaying diagnosis.
The second—and perhaps greatest—challenge is the poor prognosis of patients with advanced-stage or relapsed/refractory disease.
These patients lack an established standard salvage therapy, and long-term survival remains disappointing. Moreover, unlike B-cell lymphomas, ENKTCL lacks a universally expressed therapeutic target comparable to CD20. Although therapies targeting pathways such as PD-1/PD-L1 and JAK-STAT are under active investigation, truly precision-based treatment remains an unmet goal.
The third challenge concerns the role of allogeneic stem cell transplantation.
For high-risk R/R patients, allo-HSCT remains the only treatment with curative potential. However, post-transplant relapse and transplant-related complications—including severe graft-versus-host disease (GVHD) and infections—continue to limit its success.
Overall, although ENKTCL management has advanced considerably, treating patients with advanced or relapsed disease remains one of the field’s greatest unmet clinical needs. Future progress will depend on developing more effective targeted and immunotherapeutic approaches while further optimizing consolidation strategies such as transplantation.
Oncology Frontier – Hematology Frontier: Your retrospective study analyzed 34 patients with R/R ENKTCL who underwent allo-HSCT and found that patients achieving complete or partial remission before transplantation experienced superior survival. In contrast, pre-transplant PD-1 inhibitor exposure, number of prior treatment lines, and plasma EBV status before transplantation were not significantly associated with OS or PFS. How should clinicians interpret these findings, and what are the implications for patient selection and transplant timing?
Director Zhihui Li:
Several findings from this study deserve particular attention.
First, patients who achieved complete remission (CR) or partial remission (PR) before transplantation experienced better survival outcomes, highlighting the importance of reducing tumor burden before allo-HSCT.
However, we do not advocate delaying transplantation indefinitely in pursuit of complete remission. Our data demonstrate that patients in partial remission also derive substantial benefit. In other words, timely transplantation is preferable to missing the optimal therapeutic window while pursuing CR.
Second, although prior treatment with PD-1 inhibitors did not appear to improve long-term survival, these results require cautious interpretation.
Patients who received PD-1 inhibitors generally had more adverse baseline characteristics, including older age and more prior lines of therapy. Therefore, the findings should not be interpreted as evidence that PD-1 inhibitors are ineffective, but rather that these patients represented an inherently higher-risk population with poorer overall prognoses.
Third, although pre-transplant plasma EBV-DNA levels were not independently associated with survival, this does not imply that EBV lacks prognostic significance.
Our results suggest that the truly important factors are a history of chronic active EBV infection (CAEBV) and post-transplant EBV reactivation, the latter being associated with a hazard ratio of 8.93.
Accordingly, clinical decision-making should emphasize a patient’s history of CAEBV and the presence of hemophagocytic lymphohistiocytosis (HLH) rather than relying solely on a single EBV-DNA measurement.
Overall, these findings suggest that transplantation should be considered earlier rather than later, with remission status serving as the primary determinant of timing rather than whether a patient has previously received PD-1 inhibitors or remains EBV-positive.
Future decision-making should integrate dynamic EBV monitoring, together with LYST and TP53 mutation status, to achieve more comprehensive individualized risk stratification.
Oncology Frontier – Hematology Frontier: Your study further identified a history of CAEBV, post-transplant EBV reactivation, and HLH-associated genetic abnormalities—particularly LYST variants—as adverse prognostic factors, while TP53 mutations were associated with post-transplant relapse. What role might these biological factors play in future ENKTCL risk stratification, and could they eventually support molecularly guided treatment decisions?
Director Zhihui Li:
We believe these findings could support several important advances in precision medicine.
First, from the EBV perspective, clinicians should regard a history of CAEBV together with post-transplant EBV reactivation as critical warning indicators throughout transplantation management, rather than focusing exclusively on a single EBV-DNA measurement.
Second, from the perspective of germline genetic susceptibility, screening for HLH-associated predisposition genes, particularly LYST, could become an important component of pre-transplant evaluation, helping identify patients at high risk for HLH and allowing individualized immunosuppressive and infection-management strategies.
Third, from the perspective of somatic genetics, TP53 mutation status could be incorporated into relapse-risk models to guide both post-transplant surveillance intensity and maintenance therapy.
By integrating these three dimensions—EBV status, germline susceptibility genes such as LYST, and somatic mutations including TP53—we envision developing a multilayered risk-stratification framework capable of categorizing patients into standard-monitoring and high-risk intensified-intervention groups.
Such an approach would help shift ENKTCL management from empirical decision-making toward molecularly driven precision medicine.
Of course, this framework will require validation and refinement through future multicenter prospective studies.
Oncology Frontier – Hematology Frontier: As immunotherapy, targeted therapy, and cellular therapies continue to evolve rapidly, the treatment paradigm for ENKTCL is changing accordingly. Based on your study and future research directions, how do you envision the role of allo-HSCT evolving? What additional studies will be needed to further improve long-term outcomes for patients with high-risk ENKTCL?
Director Zhihui Li:
Based on our findings, we believe the role of allo-HSCT in ENKTCL can be optimized in several important ways.
First, transplantation should be performed earlier.
In our study, patients had received a median of three prior treatment lines, yet transplantation still produced encouraging survival outcomes. This suggests that performing allo-HSCT earlier—after failure of first- or second-line therapy while organ function remains relatively preserved—may provide even greater benefit.
Transplantation should therefore be viewed not as a last-resort intervention, but as an integral component of the overall treatment strategy for carefully selected high-risk patients.
Second, patient selection should become increasingly precise.
Developing multidimensional risk scores incorporating EBV status, LYST, TP53, and other molecular biomarkers will help identify patients most likely to benefit from transplantation while avoiding unnecessary procedures in lower-risk individuals.
Third, conditioning regimens should be individualized.
Future studies should evaluate whether conditioning intensity can be tailored according to patient age, organ function, and molecular risk profile.
Several additional research priorities also warrant attention.
Integrating EBV infection status, germline LYST mutations, and somatic TP53 mutations may allow patients to be stratified into standard-monitoring and intensified-intervention groups, accelerating the transition from empirically based treatment toward molecularly guided precision care.
Future investigations should also explore post-transplant maintenance strategies, including hypomethylating agents and virus-specific T-cell therapies, while establishing multicenter registries to generate robust real-world evidence.
Together, these efforts have the potential to substantially improve long-term survival for patients with high-risk ENKTCL.
