Abstract

Background: ENKL without any apparent nasal involvement is termed extranasal ENKL or non-nasal ENKL. Extranasal ENKL frequently exhibits advanced stage disease and short survival. The same approaches to advanced nasal ENKL are regarded as standard for extranasal ENKL. New treatments, such as radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) or steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy, have been introduced in the treatment of ENKL during the last decade; however, therapeutic approaches and outcomes of patients with extranasal ENKL in current clinical practice are not well known.

Methods: A dataset of our recent study (NKEA Part A, UMIN000015491) was used for analysis. Data from patients with newly diagnosed ENKL who were diagnosed at 31 institutes in Japan between 2000 and 2013 were analyzed. Patients' fitness for SMILE chemotherapy was assessed using the following major inclusion criteria of the SMILE phase 2 study (SMILE-P2: J Clin Oncol 2011): age 15 - 69 years; performance status (PS) 0 - 2; WBC 3,000 or > 3,000 /mm3; lymphocyte count 500 or > 500 /mm3, platelets 75 x 109 or > 75 x 109 /L (or 50 x 109 /L in patients with bone marrow [BM] involvement and/or hemophagocytic syndrome); and no serious complications. The results of a previous multicenter retrospective study in Japan (Oshimi K, et al. Hematology 2005: diagnosed between 1994 and 1998 in Japan; 2-year overall survival [OS]: nasal, < 50%, extranasal, < 30%) were used as a historical control in survival analysis.

Results: Of 358 patients, 311 (87%) had nasal ENKL, and 47 (13%) had extranasal ENKL. The nasal and extranasal groups exhibited the following features (nasal/extranasal): male, 68%/60%; age > 60, 43%/47%; advanced stage, 19%/87%; elevated LDH, 38%/83%; ECOG PS > 1, 16%/62%; B symptom present, 40%/75%; elevated serum soluble IL-2 receptor, 54%/84%; and the prognostic index of natural killer lymphoma high-risk, 13%/94%. The median number of sites of extranodal involvement in extranasal ENKL was 2 (range, 0 - 7), and common involved extranodal sites included skin/subcutaneous tissue (n = 18), liver (n = 16), BM (n = 15), small intestine (n = 9), and lung (n = 7). Of note, all patients having cutaneous involvement did not present small intestinal involvement. Major inclusion criteria of SMILE-P2 were met in 21% (10/47) of patients with extranasal ENKL, 60% (188/311; P < 0.001) of those with nasal ENKL, and 38% (23/60; P= 0.091) of those with advanced nasal ENKL. All 6 patients with localized extranasal ENKL had stage IE disease. Primary sites included testis, duodenum, small intestine, brain, skin, and cervical lymph node. Among them, only one patient (primary testicular ENKL) received RT-2/3DeVIC (contralateral RT) after surgical resection. One patient with duodenal ENKL died without therapy. In 41 patients with advanced extranasal ENKL, 7 received SMILE as first-line therapy. CHOP-like chemotherapy was selected in 12 patients, and DeVIC-like therapy was selected in 10 patients. Six out of the 22 patients received SMILE after one course of initial chemotherapy. Six patients received combined modality therapy, and 6 received no therapy. In 40 patients with extranasal ENKL who received any therapy, the complete response (CR) rate and the overall response rate were 40% and 58%, respectively. Fourteen patients underwent hematopoietic stem cell transplantation in the first CR or partial response (PR). With a median follow-up of 5.8 years, patients with extranasal ENKL exhibited shorter OS and progression-free survival (PFS) compared with those with nasal ENKL (P < 0.001). The 2-year OS of patients with nasal ENKL was 70% (95% CI, 65 - 75%), which was superior to the historical control. In contrast, the 2-year OS of patients with extranasal ENKL was 36% (95% CI, 23 - 49%). The 5-year OS was 61% in the nasal group and 15% in the extranasal group. Three patients with extranasal ENKL experienced relapse at the nasal cavity. Two of three patients with extranasal ENKL who survived greater than 5 years had primary cutaneous ENKL.

Conclusions: Despite the advent of new treatments for ENKL, the OS of patients with extranasal ENKL remains unfavorable. New treatments are often not selected for extranasal ENKL because these patients are often unfit for radiotherapy or exhibit impaired organ function. Innovative drug therapy is needed for extranasal ENKL.

Disclosures

Yamaguchi: Takeda Phamaceuticals: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharma: Honoraria; Nippon Shinyaku: Honoraria. Suzuki: MundiPharma: Consultancy; MSD: Honoraria; Mochida Pharmaceutical: Honoraria; Novartis: Honoraria; Shionogi: Honoraria; Takeda Pharmaceuticals: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Gilead Sciences: Consultancy; Jazz Pharmaceuticals: Consultancy; Kyowa-Hakko Kirin: Honoraria; Ohtsuka: Honoraria; Chugai Pharmaceutical: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Meiji Seika Pharma: Honoraria; Sawai Pharmaceutical: Honoraria. Miyazaki: Chugai Pharmaceutical: Honoraria; Takeda Pharmaceuticals: Honoraria; Eisai: Honoraria. Takizawa: Janssen Pharmaceutical: Honoraria; Chugai Pharmaceutical: Honoraria; Kyowa Hakko Kirin: Honoraria; Takeda Pharmaceuticals: Honoraria; Meiji Seika Pharma: Honoraria, Research Funding; Celgene: Honoraria; Ono Pharmaceutical: Honoraria; MSD: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Eisai: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Asahi Kasei Pharma: Honoraria; Taisho Toyama Pharmaceutical: Research Funding; Teijin Pharma: Research Funding; Mochida Pharmaceutical: Research Funding; Asahi Kasei Pharma: Research Funding. Kobayashi: Pfizer: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi Sankyo: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Boehringer Ingelheim: Research Funding; Amgen: Research Funding; Astellas Pharma: Research Funding; Ohtsuka: Research Funding. Matsuoka: Janssen Pharmaceuticals: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Bristol-Myers Squibb: Honoraria; Nippon Shinyaku: Honoraria; Chugai Pharmaceutical: Honoraria; Kyowa Hakko Kirin: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Shire Japan: Honoraria; Takeda Pharmaceuticals: Honoraria; Eisai: Honoraria; Ono Pharmaceutical: Honoraria; Novartis: Honoraria; Fujimoto Pharmaceutical: Honoraria. Sakai: Kyowa Hakko Kirin: Honoraria, Research Funding; Takeda Pharmaceuticals: Honoraria, Research Funding; FUJIFILM RI Pharma: Honoraria; Ono Phamaceutical: Research Funding; Dainippon Pharma: Honoraria; Nihon Pharmaceutical: Honoraria; Nippon Kayaku: Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Yakult Phamaceuticals: Research Funding; Bristol-Myers Squibb: Honoraria; Taiho Phamaceutical: Research Funding; Eisai: Research Funding; Bayer: Honoraria; Celgene: Honoraria. Masaki: Meiji Seika Pharma: Research Funding; Shinogi Pharmaceutical: Research Funding; Ono Pharmaceutical: Research Funding; Asahi Kasei Pharmaceutical: Research Funding; Pfizer: Research Funding; Japan Blood Products Organization: Research Funding; Teijin Pharmaceutical: Research Funding; Chugai Pharmaceutical: Research Funding; Mitsubishi Tanabe Pharmaceutical: Research Funding; Takeda Pharmaceuticals: Research Funding; Taiho Pharmaceutical: Research Funding; Taisho Toyama Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Kyowa Hakko Kirin: Research Funding; MSD: Research Funding; Eisai: Research Funding; Astellas Pharma: Research Funding; Mochida Pharmaceutical: Research Funding. Asano: Chugai Pharmaceutical: Honoraria; Janssen Pharmaceuticals: Honoraria; Kyowa Hakko Kirin: Honoraria. Katayama: Nippon Shinyaku: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Shionogi Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda Pharmaceuticals: Honoraria, Research Funding; Shire Japan: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Taisho Toyama Pharmaceutical: Honoraria; Celgene: Honoraria; Alexion Pharmaceuticals: Honoraria; Eisai: Research Funding; Daiichi Sankyo: Research Funding; Novartis: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria; Pfizer: Honoraria, Research Funding; Novo Nordisk Pharma: Honoraria, Research Funding; Teijin Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Toyama Chemical: Research Funding; Mochida Pharmaceutical: Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.