# Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study

Source: https://onco.cc/key-papers/paper-smile-chemotherapy-nk-t-cell-lymphoma-jco-2011/  
OnCo record `paper-smile-chemotherapy-nk-t-cell-lymphoma-jco-2011` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

An asparaginase-based regimen produced a response in four out of five people with an aggressive nasal lymphoma that resists ordinary chemotherapy, and nearly all of them developed dangerously low white cell counts.

## Summary

A phase 2 study of the SMILE regimen, comprising dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide, in patients with newly diagnosed stage IV, relapsed or refractory extranodal natural killer/T-cell lymphoma, nasal type, and performance status 0 to 2. Two cycles were given as the protocol treatment and the primary endpoint was the overall response rate afterwards.

38 eligible patients were enrolled, with a median age of 47 (range 16 to 67) and a male to female ratio of 21 to 17. Twenty had newly diagnosed stage IV disease, 14 were in first relapse and four were primary refractory. The first two patients died from infections, after which eligibility was revised to require a lymphocyte count of 500 per microlitre or more; no treatment-related deaths occurred after the revision. The overall response rate was 79 per cent (90 per cent confidence interval 65 to 89) and the complete response rate 45 per cent. Of the 28 patients who completed the protocol treatment, 19 underwent haematopoietic stem-cell transplantation. One-year overall survival was 55 per cent (95 per cent confidence interval 38 to 69). Grade 4 neutropenia occurred in 92 per cent and grade 3 or 4 infection in 61 per cent.

## Fields

- Kind: Key paper
- Last checked: 2026-10-01
- Also known as: SMILE; Yamaguchi 2011
- Tags: lymphoma-evidence
- Journal: Journal of Clinical Oncology
- Year: 2011
- DOI: 10.1200/JCO.2011.35.6287
- Authors: Yamaguchi M, Kwong YL, Kim WS, et al.
- Findings: The overall response rate after two cycles of SMILE was 79 per cent (90 per cent confidence interval 65 to 89) and the complete response rate 45 per cent.; One-year overall survival was 55 per cent (95 per cent confidence interval 38 to 69).; Grade 4 neutropenia occurred in 92 per cent of patients and grade 3 or 4 infection in 61 per cent.; The first two patients died from infections, after which eligibility was revised to require a lymphocyte count of 500 per microlitre or more; no treatment-related deaths followed.; Of the 28 patients who completed protocol treatment, 19 underwent haematopoietic stem-cell transplantation.
- What it means: The regimen that made extranodal NK/T-cell lymphoma treatable. The usual explanation is that asparaginase is not a substrate of the P-glycoprotein pump this tumour expresses, which would explain why it works where anthracycline-based regimens do not; that mechanism is widely repeated but has been contradicted by at least one series.
- Caveats: Single-arm phase 2 with 38 patients, in a disease with three different clinical presentations pooled together.; Two early treatment-related deaths led to a mid-study change in eligibility, so the safety profile describes a selected population.; Nineteen of 28 patients who completed treatment went on to transplantation, which contributes to the one-year survival figure.; No ClinicalTrials.gov record was found for this study when the registry was searched on 1 October 2026.

## Sources

- Journal of Clinical Oncology 2011: https://doi.org/10.1200/JCO.2011.35.6287
- PubMed: https://pubmed.ncbi.nlm.nih.gov/21990393/
- Europe PMC: https://europepmc.org/article/MED/21990393
- P-glycoprotein expression in untreated extranodal NK/T-cell lymphoma, American Journal of Hematology 2008: https://doi.org/10.1002/ajh.21256
- No correlation between P-glycoprotein and chemotherapy resistance in nasal NK/T-cell lymphoma, Leukemia and Lymphoma 2004: https://doi.org/10.1080/10428190410001693524

## Connected records

- roadmaps: [Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting](https://onco.cc/roadmaps/lymphoma-roadmap/)
- cancers: [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma)](https://onco.cc/cancers/peripheral-t-cell-lymphoma/)
- fronts: [Chemotherapy](https://onco.cc/fronts/chemotherapy/)
- drugs: [Asparaginase (pegaspargase, calaspargase pegol, Erwinia asparaginase)](https://onco.cc/drugs/asparaginase/), [Dexamethasone](https://onco.cc/drugs/dexamethasone/), [Etoposide](https://onco.cc/drugs/etoposide/), [Ifosfamide](https://onco.cc/drugs/ifosfamide/), [Methotrexate](https://onco.cc/drugs/methotrexate/)
- terms: [Autologous stem cell transplant (ASCT)](https://onco.cc/terms/autologous-transplant/), [Complete response](https://onco.cc/terms/complete-response/), [Objective response rate (ORR)](https://onco.cc/terms/orr/)
- trials: [SMILE](https://onco.cc/trials/smile-enktl/)
- bottlenecks: [Most of the world has almost no cancer care](https://onco.cc/bottlenecks/b-global-access/), [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/)
- journals: [Journal of Clinical Oncology](https://onco.cc/journals/jco/)
- ideas: [Randomised evidence for the T-cell lymphomas, including the ones that are not in Europe or North America](https://onco.cc/ideas/lymphoma-ev-randomised-evidence-for-the-t-cell-lymphomas/), [The drugs that cure lymphoma, and the places that do not have them](https://onco.cc/ideas/lymphoma-ev-the-drugs-that-cure-and-the-places-without-them/)

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