Clinical implications of plasma Epstein-Barr virus DNA in early-stage extranodal nasal-type NK/T-cell lymphoma patients receiving primary radiotherapy

The clinical value of plasma Epstein-Barr virus (EBV) DNA has not been evaluated in patients with early-stage extranodal nasal-type NK/T-cell lymphoma (NKTCL) receiving primary radiotherapy. Fifty-eight patients with stage I disease and 11 with stage II disease were recruited. High pretreatment EBV-DNA concentrations were associated with B-symptoms, elevated lactate dehydrogenase levels, and a high International Prognostic Index score. EBV-DNA levels significantly decreased after treatment. The 3-year overall survival (OS) rate was 82.6% for all patients. Stage I or II patients with a pretreatment EBV-DNA level of ≤ 500 copies/mL had 3-year OS and progression-free survival (PFS) rates of 97.1% and 79.0%, respectively, compared with 66.3% (P = .002) and 52.2% (P = .045) in patients with EBV-DNA levels of > 500 copies/mL. The 3-year OS and PFS rates for patients with undetectable EBV-DNA after treatment was significantly higher than patients with detectable EBV-DNA (OS, 92.0% vs 69.8%, P = .031; PFS, 77.5% vs 50.7%, P = .028). Similar results were observed in stage I patients. EBV-DNA levels correlate with tumor load and a poorer prognosis in early-stage NKTCL. The circulating EBV-DNA level could serve both as a valuable biomarker of tumor load for the accurate classification of early-stage NKTCL and as a prognostic factor.     

High infiltration of CD20+ B lymphocytes in extranodal natural killer/T-cell lymphoma is associated with better prognosis

Immune cells have an uncertain function during the progression of extranodal natural killer/T-cell lymphoma (ENKTL). The present study determined the distribution, phenotype, and clinical significance of B lymphocytes in ENKTL. Immunohistochemistry indicated high infiltration of CD20⁺ B lymphocytes in the tumour tissues of 40% of the patients, and that a high infiltration correlated with better overall survival. Moreover, B lymphocytes had an active mature phenotype in situ and suppressed the proliferation of ENKTL cells in vitro. These results suggest that tumour infiltration of CD20⁺ B lymphocytes may be a new prognostic indicator for patients with ENKTL.     

Treatment of advanced extranodal NK/T cell lymphoma,nasal-type and aggressive NK-cell leukemia

Extranodal NK/T cell lymphoma, nasal type (ENKL) with advanced stage and aggressive NK-cell leukemia (ANKL) are highly aggressive neoplasms with a dismal clinical outcome. It is well known that P-glycoprotein, which is a product of MDR1 gene and related to multi-drug resistance, is expressed on tumor cells of ENKL or ANKL. This is a major reason for the refractoriness to conventional chemotherapeutic regimens for malignant lymphoma containing anthracycline. However, recent studies have identified that several drugs including l-asparaginase, methotrexate and alkylators show excellent effect for these tumors. The SMILE (steroid, methotrexate, ifosfamide, l-asparaginase and etoposide) regimen is one of the promising regimens for advanced or relapsed/refractory ENKL, but its myelotoxicity is strong. ANKL needs another treatment strategy because of a systemic disease progression and extensive organ insufficiency. Optimal treatment scheme using such effective agents for these unfavorable NK-cell tumors should further be explored.     

Risk-based,response-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma in the modern chemotherapy era: A China Lymphoma Collaborative Group study

We aimed to determine the survival benefits of chemotherapy (CT) added to radiotherapy (RT) in different risk groups of patients with early-stage extranodal nasal-type NK/T-cell lymphoma (ENKTCL), and to investigate the risk of postponing RT based on induction CT responses. A total of 1360 patients who received RT with or without new-regimen CT from 20 institutions were retrospectively reviewed. The patients had received RT alone, RT followed by CT (RT + CT), or CT followed by RT (CT + RT). The patients were stratified into different risk groups using the nomogram-revised risk index (NRI). A comparative study was performed using propensity score-matched (PSM) analysis. Adding new-regimen CT to RT (vs RT alone) significantly improved overall survival (OS, 73.2% vs 60.9%, P < .001) and progression-free survival (PFS, 63.5% vs 54.2%, P < .001) for intermediate-risk/high-risk patients, but not for low-risk patients. For intermediate-risk/high-risk patients, RT + CT and CT + RT resulted in non-significantly different OS (77.7% vs 72.4%; P = .290) and PFS (67.1% vs 63.1%; P = .592). For patients with complete response (CR) after induction CT, initiation of RT within or beyond three cycles of CT resulted in similar OS (78.2% vs 81.7%, P = .915) and PFS (68.2% vs 69.9%, P = .519). For patients without CR, early RT resulted in better PFS (63.4% vs 47.6%, P = .019) than late RT. Risk-based, response-adapted therapy involving early RT combined with CT is a viable, effective strategy for intermediate-risk/high-risk early-stage patients with ENKTCL in the modern treatment era.     

Clinical features and treatment outcome of nasal-type NK/T-cell lymphoma of Waldeyer ring

The clinical characteristics and prognosis remain unclear for nasal-type NK/T-cell lymphoma of Waldeyer ring (WR-NKTL). The aim of this study is to determine the clinical features and outcome. Ninety-one patients with WR-NKTL were reviewed. According to the Ann Arbor system, 15, 56, 12, and 8 patients had stage I, II, III, and IV. Of patients with stage I and II, 54 received combined chemotherapy and radiotherapy (CMT), 13 received radiotherapy alone, and 4 patients received chemotherapy alone. All 20 patients with stage III/IV received primary chemotherapy. The disease is characterized by predominance in young males, good performance, a propensity for nodal involvement, frequent stage II through IV diseases, low frequency of elevated LDH, low-risk international prognostic index (IPI), high sensitivity to radiotherapy, and intermediate sensitivity to chemotherapy. The 5-year overall survival and progression-free survival for all patients were 65% and 51%, respectively. The age, B symptoms, stage, and IPI were important prognostic factors. CMT tended to improve the survival compared with radiotherapy alone for patients with stage I and II diseases. Both nodal involvement and distant extranodal dissemination were the primary failure patterns. WR-NKTL appears to have distinct clinical characteristics and favorable outcomes.     

Expression of CD94/NKG2A and killer immunoglobulin-like receptors in NK cells and a subset of extranodal cytotoxic T-cell lymphomas

Thirty-two natural killer (NK) and cytotoxic T-cell lymphomas and 14 noncytotoxic nodal T-cell lymphoma controls were immunostained with the use of monoclonal antibodies reactive against NK-cell receptor (NKR) molecules (CD94, NKG2A, p58.2, p58.1, p140, p70, p50.3). All NK-cell lymphomas (4 nasal/oral and 1 intestinal) expressed at least 1 NKR, the CD94/NKG2A complex. Two were positive for 1 or more killer immunoglobulin-like receptors. Of 15 extranodal cytotoxic T-cell lymphomas, 3 expressed CD94, including 2 intestinal and 1 hepatosplenic gammadelta T-cell lymphomas. In contrast, none of the nodal lymphomas were positive. Detection of NKRs may provide a useful tool to confirm the diagnosis of NK-cell lymphomas and to delineate a subgroup of cytotoxic T-cell lymphomas. Expression of NKRs only in extranodal cytotoxic T-cell lymphomas might reflect differences in the homing capabilities of cytotoxic T cells expressing NKRs in normal individuals and might be influenced in part by localized chronic immune reactions.     

Gastrosplenic fistula occurring in lymphoma patients: Systematic review with a new case of extranodal NK/T-cell lymphoma

AIM To provide the overall spectrum of gastrosplenic fistula(GSF) occurring in lymphomas through a systematic review including a patient at our hospital.METHODS A comprehensive literature search was performed in the MEDLINE database to identify studies of GSF occurring in lymphomas. A computerized search of our institutional database was also performed. In all cases, we analyzed the clinicopathologic/radiologic features, treatment and outcome of GSF occurring in lymphomas. RESULTS A literature search identified 25 relevant studies with 26 patients. Our institutional data search added 1 patient. Systematic review of the total 27 cases revealed that GSF occurred mainly in diffuse, large B-cell lymphoma(n = 23), but also in diffuse, histiocytic lymphoma(n = 1), Hodgkin's lymphoma(n = 2), and NK/T-cell lymphoma(n = 1, our patient). The common clinical presentations are constitutional symptoms(n = 20) and abdominal pain(n = 17), although acute gastrointestinal bleeding(n = 6) and infection symptoms due to splenic abscess(n = 3) are also noted. In all patients, computed tomography scanning was very helpful for diagnosing GSF and for evaluating the lymphoma extent. GSF could occur either post-chemotherapy(n = 10) or spontaneously(n = 17). Surgical resection has been the most common treatment. Once patients have recovered from the acute illness status after undergoing surgery, their long-term outcome has been favorable. CONCLUSION This systematic review provides an overview of GSF occurring in lymphomas, and will be helpful in making physicians aware of this rare disease entity.     

Advances in the management and monitoring of extranodal NK/T-cell lymphoma, nasal type

Extranodal natural killer (NK)/T-cell lymphoma, nasal type, has a unique geographic distribution. Its pathology is characterized by marked angio-invasion and tissue necrosis. A typical NK-cell phenotype is usually present: CD2⁺, CD3 epsilon+, CD56⁺, cytotoxic molecules+ and Epstein–Barr virus (EBV)+. Magnetic Resonance Imaging helps to clearly define the local involvement. Positron Emission Tomography helps to demonstrate system spread. Various prognostic variables (International Prognostic Index or the Korean Prognostic Index) should be documented. This may include quantification of plasma EBV DNA. For localized nasal disease, radiotherapy is important, although chemotherapy is often added. Sustainable remission is observed in over half of these patients. For extra-nasal or disseminated disease, systemic chemotherapy becomes the mainstay and the prognosis is usually poor. Doxorubicin-containing regimens are not entirely satisfactory and l -asparaginase containing regimens are being investigated. Patients with poor prognostic features may be considered for an early autologous haematopoietic stem cell transplant. Allogenetic transplantation is efficacious but is associated with high transplant-related mortality.     

CT of nasal-type T/NK cell lymphoma in the lung

Nasal-type T-cell/natural killer cell lymphoma is a new distinctive clinicopathologic entity with a characteristic immunophenotypic expression of CD56. Most cases show a predilection for the nasopharyngeal region and are referred to as nasal T/NK-cell lymphoma. Few cases occur in areas other than the nose. To the best of our knowledge, nasal type T/NK cell lymphoma with isolated lung involvement has not been reported. We illustrate here the CT findings of this rare tumor occurring primarily in the lung.     

Comparison analysis of first-line asparaginase- versus non-asparaginase-based regimens for early-stage extranodal NK/T-cell lymphoma

Annals of Hematology - The present study investigated the efficacy and toxicity profile of first-line asparaginase (ASP)-based versus non-ASP-based regimens in treating early-stage extranodal...     

L-Asparaginase in the treatment of refractory and relapsed extranodal NK/T-cell lymphoma, nasal type

There is no standard salvage regimen for patients with refractory and relapsed extranodal NK/T-cell lymphoma (NKTCL), nasal type. This study was conduced to evaluate the efficacy of L-asparaginase-based regimen as a salvage regimen, on refractory and relapsed extranodal NKTCL, nasal type. Between March 1996 and March 2008, 45 patients with refractory and relapsed extranodal NKTCL, nasal type, were studied retrospectively. All patients were treated with L-asparaginase-based salvage regimen. Thirty-nine patients also received primary involved-field radiation after L-asparaginase-based chemotherapy. The complete response rate, partial response rate, and overall response rate for the whole group were 55.6%, 26.7%, and 82.2%, respectively. Both of 3-year and 5-year overall survival (OS) rates were 66.9%. The major adverse effects of L-asparaginase were myelosuppression, liver dysfunction, hyperglycemia, and allergic reaction. In general, the side effects could be tolerated. On univariate analysis, age, the stage of disease, and performance status were found to be prognostic factors influencing OS. On multivariate analysis, the stage of disease and age were independent prognostic factors for OS. L-Asparaginase-based regimen was obviously effective for the patients with refractory and relapsed extranodal NKTCL, nasal type.     

原发性肺结外鼻型NK/T细胞淋巴瘤一例临床分析

目的报道国内第一例肺部原发性结外鼻型NK/T淋巴瘤,分析原发性肺鼻型NK/T淋巴瘤的临床特点和诊断治疗。方法通过1例病理证实的原发性肺结外鼻型淋巴瘤的病例分析,结合文献,对原发性肺NK/T淋巴瘤的免疫表型、发病机制、临床特点、影像学表现、诊断、治疗及预后进行分析。结果NK/T细胞淋巴瘤是一种新近认识的恶性淋巴瘤,原发于肺部的比较罕见,具有特殊的免疫表型与临床病理特点,EB病毒在其发病中扮演重要角色。此瘤恶性程度很高,疾病进展快,治疗效果及预后差。结论原发性肺结外鼻型NK/T淋巴瘤临床罕见,诊断难度大,预后差,目前缺少有效的治疗方法。     

First-line immunotherapy with anti-PD-1 antibody for extranodal NK/T-cell lymphoma: A retrospective study

Anti-PD-1 antibody has shown certain effects in patients with newly diagnosed extranodal NK/T-cell lymphoma (ENKTL). Here, we evaluated the clinical efficacy and safety of first-line anti-PD-1 antibody for the treatment of patients with ENKTL and explored biomarkers for treatment response. The clinical data of 107 patients with newly diagnosed ENKTL were retrospectively analysed. Patients received either first-line anti-PD-1 antibody induction treatment or anti-PD-1 antibody combined with asparaginase-based chemotherapy (immunochemotherapy). We found that immunochemotherapy was an independent prognostic factor for longer PFS (p < 0.001). The overall response rate and complete remission rate of immunochemotherapy group was higher than immunotherapy induction group (86.11% vs. 62.86% and 72.22% vs. 52.29%, respectively, p = 0.013). We also observed pretreatment CD4/CD8 ratio >0.83 was significant associated with better response and longer PFS in ENKTL patients received first-line anti-PD1-antibody. Plasma copy number of EBV decreased more significantly in patients with CD4/CD8 ratio >0.83 after treatment. PD-L1 expression was associated with better response and PFS, while elevated plasma IL-6, IL-10 and IFN-γ were associated with poor prognosis. Anti-PD-1 antibody treatment showed promising results in newly diagnosed ENKTL patients. The assessment of pretreatment CD4/CD8 ratio in ENKTL seems feasible for identifying responders to anti-PD-1 antibody treatment.