Recent advances in the diagnosis and treatment of natural killer/T-cell lymphomas

ABSTRACT

Introduction: Natural killer (NK)/T-cell lymphomas are aggressive malignancies that present predominantly in nasal and adjacent sites (nasal subtype), occasionally in skin, gastrointestinal tract and other tissues (non-nasal), and rarely as disseminated disease with a leukemic phase (aggressive NK-cell leukemia, or leukemia/lymphoma, subtype).

Areas covered: The diagnosis and treatment of NK/T-cell lymphoma are discussed, based on a PubMed literature search. The diagnostic criteria for NK/T-cell lymphoma are highlighted, followed by an update of the diagnostic and prognostic importance (on presentation, at interim and end-of-treatment) of plasma EBV DNA as a surrogate biomarker of lymphoma load. Prognostic models based on clinicopathologic features and EBV DNA load are discussed. For stage I/II NK/T-cell lymphomas, combined chemotherapy, and radiotherapy gives the best results, with their concomitant or sequential administration equally efficacious. For stage III/IV NK/T-cell lymphoma, chemotherapy is the mainstay of treatment. Conventional anthracycline-based regimens for B-cell lymphomas are ineffective. Recommended regimens combine L-asparaginase with other drugs not affected by P-glycoprotein. For relapsed/refractory patients, immune checkpoint blockade with antibodies against programmed cell death protein 1 has shown much promise.

Expert opinion: Current strategies result in durable remissions in a significant proportion of NK/T-cell lymphomas. Immune checkpoint inhibition and other novel approaches are promising for relapsed/refractory cases.

KEYWORDS:

• NK/T-cell lymphoma
• Epstein Barr virus
• L-asparaginase
• hematopoietic stem cell transplantation
• programmed cell death protein 1

Article highlights

• NK/T-cell lymphomas are mostly of NK-cell derivation, and occasionally of bona fide T-cell derivation.

• Clinically, they can be divided in nasal, non-nasal, and disseminated (lymphoma/leukemia) subtypes.

• All NK/T-cell lymphomas are infected by Epstein Barr virus (EBV).

• Plasma EBV DNA, derived from apoptosis of NK/T-cell lymphoma cells, is an accurate biomarker of lymphoma load.

• Positron emission tomography-computed tomography is the standard imaging technique and is of diagnostic and prognostic (interim and end-of-treatment) significance.

• Conventional anthracycline-containing regimens are ineffective because of the expression of P-glycoprotein in NK/T-cell lymphoma cells.

• Current effective regimens comprise L-asparaginase and other drugs not affected by P-glycoprotein.

• Stage I/II NK/T-cell lymphomas are treated by combined chemotherapy and radiotherapy, with their concurrent or sequential administration equally efficacious.

• Stage III/IV NK/T-cell lymphomas are treated by chemotherapy.

• Autologous hematopoietic stem cell transplantation (HSCT) is of limited utility in NK/T-cell lymphomas.

• Allogeneic HSCT can be considered in selected stage III/IV patients.

• The programmed cell death protein ligand 1 (PDL1) is over-expressed in NK/T-cell lymphomas, due to EBV infection and genetic alterations leading to JAK/STAT pathway activation; which may be a mechanism of immune evasion.

• Immune checkpoint inhibition by blockade of the programmed cell death protein 1 on effector T cells is a promising therapy for relapsed/refractory NK/T-cell lymphomas.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A peer reviewer on this manuscript has acted as consultant for Seattle Genetics. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.