# SMILE

Source: https://onco.cc/trials/smile-enktl/  
OnCo record `smile-enktl` (Trial). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

An asparaginase-based regimen gave a response in four out of five people with an aggressive nasal lymphoma that had always resisted standard chemotherapy, and nearly all of them had dangerously low white cell counts.

## Summary

Extranodal natural killer/T-cell lymphoma, nasal type, is driven by Epstein-Barr virus and is concentrated in east Asia and Latin America. Anthracycline-based regimens such as CHOP fail in it, and every regimen that works is built on asparaginase. The explanation usually given is that the tumour expresses P-glycoprotein, a pump that expels anthracyclines but not asparaginase; immunohistochemical expression has been documented (Wang, American Journal of Hematology 2008), but a Korean series found no correlation between P-glycoprotein and chemotherapy resistance (Kim, Leukemia and Lymphoma 2004), so the mechanism is the accepted account rather than a settled one.

The NK-Cell Tumor Study Group tested SMILE, a five-drug regimen of dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide, in 38 eligible patients with newly diagnosed stage IV, relapsed or refractory disease. The first two patients died of infection, after which eligibility was tightened to require a lymphocyte count of 500 per microlitre or more, and no further treatment-related deaths occurred. After two cycles 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 went on to 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. SMILE is therefore a regimen for a patient who can be supported through profound myelosuppression, and the eligibility amendment is part of the result rather than a footnote to it. The disease has no cancer record of its own in OnCo yet; it is attached here to peripheral T-cell lymphoma.

## Fields

- Kind: Trial
- Status: positive
- Last checked: 2026-10-01
- Also known as: SMILE regimen; SMILE chemotherapy for extranodal NK/T-cell lymphoma
- Tags: lymphoma-evidence
- Phase: 2
- Setting: Newly diagnosed stage IV, relapsed or refractory extranodal natural killer/T-cell lymphoma, nasal type: two cycles of dexamethasone, methotrexate, ifosfamide, asparaginase and etoposide
- Sponsor: NK-Cell Tumor Study Group
- Enrolled: 38
- Result: Overall response 79 per cent and complete response 45 per cent after two cycles, one-year overall survival 55 per cent, with grade 4 neutropenia in 92 per cent.
- Outcomes: Overall response rate after two cycles: SMILE 79%; Overall survival at 1 year: SMILE 55%
- Replication: Asparaginase-based regimens have since been compared with each other in Chinese and Korean trials; the principle that anthracyclines fail and asparaginase works has held.

## Sources

- Journal of Clinical Oncology 2011: https://doi.org/10.1200/JCO.2011.35.6287

## Connected records

- 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/)
- 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/)
- key papers: [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](https://onco.cc/key-papers/paper-smile-chemotherapy-nk-t-cell-lymphoma-jco-2011/)
- 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/)
- 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/)
- trials: [ECHELON-2](https://onco.cc/trials/echelon-2/)

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