Pretreatment EBV-DNA Copy Number Is Predictive for Response to SMILE Chemotherapy for Newly-Diagnosed Stage IV, Relapsed or Refractory Extranodal NK/T-Cell Lymphoma, Nasal Type: Results of NKTSG Phase II Study

Extranodal NK/T-cell lymphoma, nasal type (ENKL) is a rare subtype of lymphoma and its standard therapy is not established. Because of the expression of multi-drug resistance associated P-glycoprotein, CHOP (-like) chemotherapy has limited efficacy in ENKL, with an overall response rate (ORR) of 36% for newly-diagnosed stage IV diseases and less than 10% for relapsed or refractory diseases. Our previous phase I trial of a new chemotherapeutic regimen, SMILE (Steroid=dexamethasone, Methotrexate, Ifosfamide, L-asparaginase and Etoposide) showed promising results (Cancer Sci, 2008). ENKL is invariably associated with clonal episomal infection of Epstein-Barr virus (EBV) in the lymphoma cells. The peripheral blood of these patients contains fragmented EBV-DNA, which can be used as a quantitative surrogate tumor marker for disease diagnosis, monitoring and prognostication.

A phase II study of SMILE chemotherapy was conducted. Patients (Pts) with newly-diagnosed stage IV, or relapsed/refractory disease after first-line chemotherapy, between 15–69 years old and with a PS of 0–2 were eligible. Primary endpoint was ORR after 2 cycles of SMILE chemotherapy, and target enrollment was 38 pts. To ameliorate myelotoxicity and based on the results of phase I study, G-CSF was started from day 6. A part of this study (anti-tumor effect of the SMILE chemotherapy) has been presented in ASCO 2010 (abstract #8044) and EHA 2010 (abstract #299) meetings. EBV-DNA copy number before treatment was analyzed by using quantitative polymerase chain reaction. In Japan, the EBV-DNA was measured at the central laboratory (Nagoya Univ.). In Hong Kong and Korea, it was measured in each country, and was converted using coefficients. The association of converted EBV-DNA and anti-tumor effect of SMILE chemotherapy was investigated.

From July 2007 to October 2009, a total of 39 pts were enrolled in the phase II SMILE study. The median age was 47 years (range: 16–67), and male/female ratio was 21/18. There were newly-diagnosed stage IV disease in 21, first relapse in 13, and primary refractory disease in 5 pts. EBV-DNA before treatment was measured in 38 patients using whole blood (N=34) or plasma/serum (N=33). In 29 patients the EBV-DNA was examined in both samples. The median EBV-DNA was 2,850 copies/mL (range: 0–1.14×10^7) in whole blood and 1,101 copies/mL (range: 0–1.27×10^7). Results of these 2 measurement of EBV-DNA well correlated (r = 0.8706, P < 0.0001). EBV-DNA was undetectable (below the cutoff level) in 7 of 34 patients using whole blood and 14 of 33 patients using plasma/serum. 29 pts (74%) completed the planned treatment. The responses were complete remission (CR) in 15, partial remission (PR) in 14, no response in 4, progressive disease in 3, and early death in 3. ORR and %CR were 74% (90% confidence interval, 60–85) and 38%, respectively. Grade 4 neutropenia occurred in 36 of 39 patients (92%), and 2 patients died of infection during neutropenia. Grade 4 non-hematologic toxicities were infection (n=5), hyperbilirubinemia (n=1), ALT elevation (n=2) and encephalopathy (n=1). The grade 4 non-hematologic toxicity was only experienced in the 1st course of SMILE. No patient developed grade 4 non-hematologic toxicity in the 2nd course. The most common grade 3 non-hematologic toxicity was infection (41%). The whole blood EBV-DNA copy number was associated with ORR (r=0.71) and %CR (r=0.78). ORR was 88% in patients with less than 10^5 copies/mL EBV-DNA in whole blood, but was 44% in patients with more than 10^5 copies/mL (P=0.02). Six of 7 patients without detectable EBV-DNA in whole blood attained CR. In contrast, none of the 8 patients with more than 10^5 copies/mL EBV-DNA could achieve CR. Grade 4 non-hematologic toxicity was significantly higher in patients with more than 10^4 copies/mL of EBV-DNA in plasma (55% vs. 14%, P=0.03).

Our results indicate that SMILE chemotherapy is an effective treatment for newly-diagnosed stage IV, relapsed or refractory ENKL. Myelosuppression and infection during the treatment should carefully be managed. EBV-DNA copy number is also predictive for response and adverse events of SMILE chemotherapy for newly-diagnosed stage IV, relapsed or refractory ENKL.

Suzuki:Kyowa Kirin Company: Honoraria. Oshimi:Eisai Pharmaceutical Co Ltd: Employment.