Treatment of extranodal NK/T-cell lymphoma: From past to future

Abstract

Extranodal NK/T-cell lymphoma (ENKTCL) is the most common subtype of T/NK-cell lymphoma in Asia and Latin America, but very rare in North American and Europe. Patient survival has improved significantly over the past two decades. However, standard treatment has not yet been established, although dozens of prospective trials have been conducted. To help understand how the treatment of ENKTCL has evolved in the past and what trends lie ahead, we have comprehensively reviewed the treatment of this aggressive malignancy, with a particular focus on neglected or unanswered issues, such as the optimal staging method, the best partner of asparaginase (Asp), the individualized administration of Asp, the preferred sequence of CT and RT and so on. Overall, the 5-year overall survival (OS) of patients with Ann Arbor stage I/II disease increased from < 50% in the early 20th century to > 80% in recent years, and the median OS of patients with Ann Arbor stage III/IV disease increased from < 1 year to more than 3 years. The improvement in patient survival is largely attributable to advances in radiation technology and the introduction of Asp and anti-PD-1/PD-L1 immunotherapy into practice. Radiotherapy is essential for patients with early-stage disease, while Asp-based chemotherapy (CT) and PD-1/PD-L1 inhibitors significantly improved the prognosis of patients with advanced-stage disease. ENKTCL management is trending toward simpler regimens, less toxicity, and higher efficacy. Novel drugs, such as manufactured T cells, monoclonal antibodies, and small molecule inhibitors, are being intensively investigated. Based on the fact that ENKTCL is highly resistant to cytotoxic drugs except Asp, and aggressive CT leads to higher toxicity rather than better outcomes, we recommend it is unnecessary to expend additional resources to compare different combinations of Asp with cytotoxic agents. Instead, more efforts should be made to optimize the use of Asp and immunotherapy to maximize efficacy and minimize toxicity, explore ways to overcome resistance to Asp and immunotherapy, identify novel treatment targets, and define subpopulations who may benefit more from specific treatments.

Keywords: PD-1/PD-L1 inhibitor; asparaginase; extranodal NK/T-cell lymphoma; immunotherapy; novel drug; review; treatment.

Figure 1

Milestones in the recognition (shown in yellow below the timeline) and treatment (shown in green above the timeline) of ENKTCL.

Figure 2

Survival trends of patients with Ann Arbor stage I/II ENKTCL over the past two decades. Only data from patients treated with RT or RT plus CT are included. The area of each marker in the figure indicates the sample size of the study. Data are cited from (–97).

Figure 3

Complete response (CR) rate and progression-free survival (PFS) of patients with Ann Arbor stage III/IV or relapsed/refractory ENKTCL treated with different drug types. Asp, asparaginase; Asp-R, asparaginase-resistant; Anth, anthracycline; Anth-R, anthracycline-resistant; CT, chemotherapy; TN, treatment naïve; OS, overall survival (when PFS is not available, OS is displayed); y, year; H, hematopoietic stem cell transplantation. The area of each marker in the figure indicates the sample size of the study. Data are cited from (, , , , , , , , –114).

Figure 4

Overview of the mechanism of action of asparaginase (Asp) against NK/T-cell lymphoma (NKTCL). Due to the lack of asparagine synthetase (AsnS), NKTCL cells depend on the uptake of extracellular L-asparagine from the circulation (pathway ①) for protein synthesis. Administration of Asp hydrolyzes serum asparagine to aspartic acid and ammonia (NH3), thereby inhibiting tumor cell protein synthesis and ultimately leading to tumor cell death. In contrast, all normal cells in the body have two pathways to obtain L-asparagine for protein synthesis: taking extracellular L-asparagine from the circulation (pathway ①) and synthesizing their own L-asparagine from aspartic acid and NH3 via AsnS (pathway ②). When pathway ① is blocked, normal cells can still obtain adequate L-asparagine via pathway ② to meet their metabolic needs.

Figure 5

OS trends in early-stage ENKTCL patients treated with different modalities. CT, chemotherapy; RT, radiotherapy; Anth, anthracycline; CRT, chemoradiotherapy; Asp, asparaginase; PEG-Asp, pegaspargase; OS, overall survival. Data cited from (, –, –, , , –, –, –97).

Figure 6

PEG-Asp activity monitoring algorithm for assessing possible silent inactivation by neutralizing antibodies and/or accelerated clearance (137).

Figure 7

Schematic illustration of targeted therapies in ENKTCL. Green indicates that the targeted therapies have been widely used in practice; cyan indicates that the therapies are being investigated in early-stage clinical trials; orange indicates that the therapies have shown activity in animal models; and red indicates that the therapies are currently under investigation in clinical trials.