Modified SMILE in the Treatment of Natural Killer T-Cell Lymphoma, Nasal and Nasal Type: A Single Center US Experience

Extranodal NK/T cell lymphoma (ENKL) is a rare subtype of peripheral T cell lymphoma. The treatment of ENKL is largely dependent upon the extent of disease at the time of presentation. Historically these tumors have shown poor responsiveness to chemotherapy and patients with localized disease are often treated primarily with radiotherapy. Overall survival is poor for those with advanced disease. Recent studies exploring the use of L-asparaginase alone or in combination with other cytotoxic chemotherapy has led to significant response rates in the up-front and relapsed/refractory setting. The novel regimen SMILE (steroid=dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) appears particularly active in ENKL (Yamaguchi M Cancer Sci 2008; 99: 1016–1020). We report our experience in consecutive untreated patients using a modification of SMILE (mSMILE) in which a single dose of pegylated-L-asparaginase is substituted for 6 doses of L-asparaginase per cycle and the cycle length shortened to 3 weeks.

Starting in 9/09 the MSKCC lymphoma service began adopting mSMILE (Steroid=dexamethasone 40 mg IVPB days 2–4, methotrexate 2000 mg/m² day 1, ifosfamide 1500 mg/m² days 2–4, pegylated-L-asparaginase 2500 IU/m² IVPB day 8, and etoposide 100 mg/m² days 2–4) for treatment of our patients with newly diagnosed ENKL. Cycles of chemotherapy were repeated approximately every 3 weeks and all patients received growth factor support. Each patient's disease status was established by ENT direct examination, PET/CT, and bone marrow biopsy. Patients with localized (L) disease (I, IE) were intended to receive mSMILE for two cycles prior to consolidative radiotherapy. Patients with locally advanced (LA) or disseminated (D) disease were intended to receive 2 to 3 cycles of mSMILE along with radiotherapy to bulky original sites with high dose chemotherapy and stem cell transplantation as consolidation. Primary response evaluations were PET/CT for all patients after 1–2 cycles of mSMILE.

Eight patients with newly diagnosed ENKL were seen between 09/09 and 07/11. Seven had nasal ENKL and 1 had ENKL-nasal type. Extent of disease was: L=5, LA=1, D=2. Patient characteristics were: age median 43.5 (24–64); male:female=5:3; Caucasian-5 (Latino-2) and Asian-3. Treatment was as follows: two cycles of mSMILE followed by involved field radiation therapy to 45 cGy (n=5), mSMILE for 3 cycles in locally advanced (n=1) and disseminated disease (n=2) along with radiotherapy to prior bulky sites followed by either autologous (n=1) or allogeneic (n=2) stem cell transplantation. Responses to mSMILE after at 1–2 cycles by PET/CT were: overall response rate 100% (8/8), complete response (CR) 88% (7/8), and partial response (PR) 12% (1/8). Toxicities were grade 3–4 neutropenia (n=6), grade 3–4 anemia (n=2), grade 3–4 thrombocytopenia (n=2), grade 3 nausea and vomiting (n=3), upper respiratory infection (n=2), syncope (n=1), and febrile neutropenia (n=1). All patients had increased LFTs during treatment (grade 3–4 n=1), all resolved to safe pre-treatment levels prior to the next cycle and did not affect dosing or drug administration. At median follow-up of 5.5 months (range 2–23) 7 patients are alive. Five are alive in remission post therapy for a median of 14 months (range 4–23) and 2 patients (1CR; 1PR) are currently undergoing radiotherapy after responding to mSMILE. One patient with disseminated disease died in remission at day +83 post allogeneic stem cell transplant of tacrolimus induced TTP.

We report our experience in 8 consecutive patients treated with mSMILE for newly diagnosed ENKL. This is the first series of patients treated with this approach outside of Asia. In this data set 88% of patients achieved a CR rate after 1–2 cycles of mSMILE. This intensive chemotherapy regimen carries significant hematologic toxicity. Our modification of substituting pegylated L-asparaginase on day 8 and using growth factors in order to treat on an every three-week basis allowed patients to maintain intended dose intensity. Ultimately, a larger study is needed to validate our observation. However, the activity shown to date suggests this is a more active regimen than those previously used such as CHOP and carries the potential to improve outcomes in these patients.

Horwitz:Sigma Tau: Consultancy.