Section editor
	Bhagirathbhai Dholaria, MBBS Vanderbilt University Nashville, TN, USA LinkedIn

Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page.
Note: The most common subtype of this condition (ENKTCL, nasal type) has a dedicated page.

We have moved How I Treat articles to a dedicated page.

5 regimens on this page 5 variants on this page

Note: a variant of this disease, aggressive NK-cell leukemia, is usually considered a separate entity (somewhat analogous to plasma cell leukemia and multiple myeloma). There are no prospective trials reported for this variant.

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ESMO

2015: d'Amore et al. Peripheral T-cell lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

NCCN

NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - T-cell Lymphomas.

Untreated

DDGP

DDGP: Dexamethasone, DDP (Cisplatin), Gemcitabine, Pegaspargase

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Li et al. 2016 (CTTNKTL-III/IV)	2011-01 to 2019-02	Phase 4 (E-switch-ic)	SMILE	Seems to have superior OS¹ (secondary endpoint) Median OS: NYR vs 75.2 mo (HR 0.41, 95% CI 0.19-0.89) Superior PFS¹ (primary endpoint) Median PFS: NYR vs 6.8 mo (HR 0.42, 95% CI 0.23-0.77)

¹Reported efficacy is based on the 2023 update.
Note: dosing information is from the update.

Glucocorticoid therapy

Dexamethasone (Decadron) 15 mg/m² IV once per day on days 1 to 5

Chemotherapy

Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 4
Gemcitabine (Gemzar) 800 mg/m² IV over 30 minutes once per day on days 1 & 8
Pegaspargase (Oncaspar) 2500 IU/m² IM once on day 1

21-day cycle for 6 cycles

References

CTTNKTL-III/IV: Li X, Cui Y, Sun Z, Zhang L, Li L, Wang X, Wu J, Fu X, Ma W, Zhang X, Chang Y, Nan F, Li W, Su L, Wang J, Xue H, Zhang M. DDGP versus SMILE in newly diagnosed advanced natural killer/T-cell lymphoma: a randomized controlled, multicenter, open-label study in China. Clin Cancer Res. 2016 Nov 1;22(21):5223-5228. Epub 2016 Apr 8. link to original article does not contain dosing details PubMed NCT01501149
1. Update: Wang X, Zhang L, Liu X, Li X, Li L, Fu X, Sun Z, Wu J, Zhang X, Yan J, Chang Y, Nan F, Zhou Z, Wu X, Tian L, Ma M, Li Z, Yu H, Zhu L, Wang Y, Shi C, Feng X, Li J, Ding M, Zhang J, Dong M, Xue H, Wang J, Zou L, Su L, Wu J, Liu L, Bao H, Zhang L, Guo Y, Guo S, Lu Y, Young KH, Li W, Zhang M. Efficacy and Safety of a Pegasparaginase-Based Chemotherapy Regimen vs an L-asparaginase-Based Chemotherapy Regimen for Newly Diagnosed Advanced Extranodal Natural Killer/T-Cell Lymphoma: A Randomized Clinical Trial. JAMA Oncol. 2022 Jul 1;8(7):1035-1041. link to original article link to PMC article contains dosing details in manuscript PubMed

SMILE

SMILE: Steroid (Dexamethasone), Methotrexate, Ifosfamide, L-asparaginase, Etoposide

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kwong et al. 2012	2005-2012	Phase 2
Li et al. 2016 (CTTNKTL-III/IV)	2011-01 to 2019-02	Phase 4 (E-switch-ic)	DDGP	Seems to have inferior OS (secondary endpoint) Inferior PFS (primary endpoint)

¹Reported efficacy for CTTNKTL-III/IV is based on the 2023 update.
Note: Asparaginase (Elspar) was discontinued by the manufacturer in December 2012, and is now essentially out of stock. Alternatives include Pegaspargase (Oncaspar) or Asparaginase Erwinia chrysanthemi (Erwinaze).

Glucocorticoid therapy

Dexamethasone (Decadron) 40 mg PO once per day on days 2 to 4

Chemotherapy

Methotrexate (MTX) 2000 mg/m² IV over 6 hours once on day 1
Ifosfamide (Ifex) 1500 mg/m² IV over 6 hours once per day on days 2 to 4, given with mesna
Asparaginase (Elspar) 6000 units/m² IV over 2 hours once per day on days 3 to 9
- Skin test done for asparaginase before each dose; Asparaginase Erwinia chrysanthemi used for patients who developed sensitivity to L-asparaginase from E. coli
Etoposide (Vepesid) 100 mg/m² IV over 2 hours once per day on days 2 to 4

Supportive therapy

Leucovorin (Folinic acid) 45 mg PO every 6 hours on days 2 to 4 (or until serum methotrexate level is below the toxic range), starting 24 hours after completion of methotrexate
- Methotrexate levels checked at 24, 48, and 72 hours after methotrexate is given, or until methotrexate levels fall below toxic range. Folinic acid should be continued until methotrexate levels are below toxic range.
Mesna (Mesnex) 900 mg/m² IV over 6 hours once per day on days 2 to 4, given with ifosfamide
Hydration with normal saline (no volume specified) every 8 hours on the day prior to methotrexate
Patients told to drink at least 2 liters of fluid per day on days 1 to 4; target urine output of greater than or equal to 3 liters per day on days 1 to 4
Filgrastim (Neupogen) 300 mcg SC once per day, starting on day 6, given until ANC greater than 1000/μL
Cotrimoxazole or Pentamidine (Nebupent) for PJP prophylaxis
Famotidine (Pepcid) and potassium slow release tablets (no dose specified) "for Dexamethasone (Decadron)" on days 2 to 4
Chlorpheniramine (Chlor-Trimeton) 10 mg PO once per day on days 8, 10, 12, 14, 16, 18, 20, prior to asparaginase
Hydrocortisone (Cortef) 100 mg IV once per day on days 8, 10, 12, 14, 16, 18, 20, prior to asparaginase

21-day cycle for 6 cycles

References

Kwong YL, Kim WS, Lim ST, Kim SJ, Tang T, Tse E, Leung AY, Chim CS; Asia Lymphoma Study Group. SMILE for natural killer/T-cell lymphoma: analysis of safety and efficacy from the Asia Lymphoma Study Group. Blood. 2012 Oct 11;120(15):2973-80. Epub 2012 Aug 23. link to original article supplemental materials contains dosing details in supplement PubMed
CTTNKTL-III/IV: Li X, Cui Y, Sun Z, Zhang L, Li L, Wang X, Wu J, Fu X, Ma W, Zhang X, Chang Y, Nan F, Li W, Su L, Wang J, Xue H, Zhang M. DDGP versus SMILE in newly diagnosed advanced natural killer/T-cell lymphoma: a randomized controlled, multicenter, open-label study in China. Clin Cancer Res. 2016 Nov 1;22(21):5223-5228. Epub 2016 Apr 8. link to original article PubMed NCT01501149
1. Update: Wang X, Zhang L, Liu X, Li X, Li L, Fu X, Sun Z, Wu J, Zhang X, Yan J, Chang Y, Nan F, Zhou Z, Wu X, Tian L, Ma M, Li Z, Yu H, Zhu L, Wang Y, Shi C, Feng X, Li J, Ding M, Zhang J, Dong M, Xue H, Wang J, Zou L, Su L, Wu J, Liu L, Bao H, Zhang L, Guo Y, Guo S, Lu Y, Young KH, Li W, Zhang M. Efficacy and Safety of a Pegasparaginase-Based Chemotherapy Regimen vs an L-asparaginase-Based Chemotherapy Regimen for Newly Diagnosed Advanced Extranodal Natural Killer/T-Cell Lymphoma: A Randomized Clinical Trial. JAMA Oncol. 2022 Jul 1;8(7):1035-1041. link to original article link to PMC article contains dosing details in manuscript PubMed

Relapsed or refractory

AspaMetDex

AspaMetDex: Asparaginase, Methotrexate, Dexamethasone

Regimen

Study	Evidence	Efficacy
Jaccard et al. 2010 (I05009)	Phase 2	ORR: 78%

Chemotherapy

Asparaginase (Elspar) 6000 units/m² IM once per day on days 2, 4, 6, 8
Methotrexate (MTX) by the following age-based criteria:
- Younger than 70 years old: 3000 mg/m² (route not specified) once on day 1
- Older than 70 years old: 2000 mg/m² (route not specified) once on day 1

Glucocorticoid therapy

Dexamethasone (Decadron) by the following age-based criteria:
- Younger than 70 years old: 40 mg PO once per day on days 1 to 4
- Older than 70 years old: 20 mg PO once per day on days 1 to 4

Supportive therapy

Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose/route/schedule not specified) prophylaxis, discontinued during methotrexate administration
Valacyclovir (Valtrex) (dose/route/schedule not specified) prophylaxis
Alkaline hydration (type/dose/schedule not specified)
Leucovorin (Folinic acid) rescue (dose/route/schedule not specified)

21-day cycle for 3 cycles

Subsequent treatment

See paper for details about further treatment

References

I05009: Jaccard A, Gachard N, Marin B, Rogez S, Audrain M, Suarez F, Tilly H, Morschhauser F, Thieblemont C, Ysebaert L, Devidas A, Petit B, de Leval L, Gaulard P, Feuillard J, Bordessoule D, Hermine O; GELA; GOELAMS. Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood. 2011 Feb 10;117(6):1834-9. Epub 2010 Dec 1. link to original article contains dosing details in manuscript PubMed NCT00283985

AspaMetDex (Erwinaze)

AspaMetDex: Asparaginase, Methotrexate, Dexamethasone

Regimen

Study	Evidence	Efficacy
Jaccard et al. 2010 (I05009)	Phase 2	ORR: 78%

Note: this regimen is for patients with allergies to asparaginase.

Chemotherapy

Asparaginase Erwinia chrysanthemi (Erwinaze) 20,000 units/m² IM once per day on days 2, 4, 6, 8
Methotrexate (MTX) by the following age-based criteria:
- Younger than 70 years old: 3000 mg/m² (route not specified) once on day 1
- Older than 70 years old: 2000 mg/m² (route not specified) once on day 1

Glucocorticoid therapy

Dexamethasone (Decadron) by the following age-based criteria:
- Younger than 70 years old: 40 mg PO once per day on days 1 to 4
- Older than 70 years old: 20 mg PO once per day on days 1 to 4

Supportive therapy

Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose/route/schedule not specified) prophylaxis, discontinued during methotrexate administration
Valacyclovir (Valtrex) (dose/route/schedule not specified) prophylaxis
Alkaline hydration (type/dose/schedule not specified)
Leucovorin (Folinic acid) rescue (dose/route/schedule not specified)

21-day cycle for 3 cycles

Subsequent treatment

See paper for details about further treatment

References

I05009: Jaccard A, Gachard N, Marin B, Rogez S, Audrain M, Suarez F, Tilly H, Morschhauser F, Thieblemont C, Ysebaert L, Devidas A, Petit B, de Leval L, Gaulard P, Feuillard J, Bordessoule D, Hermine O; GELA; GOELAMS. Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood. 2011 Feb 10;117(6):1834-9. Epub 2010 Dec 1. link to original article contains dosing details in manuscript PubMed NCT00283985

Fludarabine, Busulfan, Cyclophosphamide, then allo HSCT

FluBuCy: Fludarabine, Busulfan, Cyclophosphamide

Regimen variant #1, oral

Study	Dates of enrollment	Evidence
Glass et al. 2014 (DSHNHL R3)	2004-06-16 to 2009-03-24	Phase 2

Chemotherapy

Fludarabine (Fludara) 25 mg/m²/day IV on days -8 to -4
Busulfan (Myleran) 4 mg/kg/day PO on days -6 to -4
Cyclophosphamide (Cytoxan) 60 mg/kg/day IV on days -3 and -2

Immunotherapy

Allogeneic stem cells transfused on day 0

GVHD prophylaxis

Antithymocyte globulin, rabbit ATG (Thymoglobulin) 2 mg/kg IV from day -3 to -1 (unclear if this is a total dose or a daily dose)
- Option also to use ATG-Fresenius S at a higher dose of 10 mg/kg
Tacrolimus (Prograf) 8 to 12 mcg/L (route/frequency not specified) starting on day -1, tapered from day +100 in absence of GVHD
Mycophenolate mofetil (CellCept) 1000 mg (route not specified) twice per day from day +1 to +28

One course

Regimen variant #2, intravenous

Study	Dates of enrollment	Evidence
Glass et al. 2014 (DSHNHL R3)	2004-06-16 to 2009-03-24	Phase 2

Chemotherapy

Fludarabine (Fludara) 25 mg/m²/day IV on days -8 to -4
Busulfan (Myleran) 3.2 mg/kg/day IV on days -6 to -4
Cyclophosphamide (Cytoxan) 60 mg/kg/day IV on days -3 and -2

Immunotherapy

Allogeneic stem cells transfused on day 0

GVHD prophylaxis

Antithymocyte globulin, rabbit ATG (Thymoglobulin) 2 mg/kg IV from day -3 to -1 (unclear if this is a total dose or a daily dose)
- Option also to use ATG-Fresenius S at a higher dose of 10 mg/kg
Tacrolimus (Prograf) 8 to 12 mcg/L (route/frequency not specified) starting on day -1, tapered from day +100 in absence of GVHD
Mycophenolate mofetil (CellCept) 1000 mg (route not specified) twice per day from day +1 to +28

One course

References

DSHNHL R3: Glass B, Hasenkamp J, Wulf G, Dreger P, Pfreundschuh M, Gramatzki M, Silling G, Wilhelm C, Zeis M, Görlitz A, Pfeiffer S, Hilgers R, Truemper L, Schmitz N; German High-Grade Lymphoma Study Group. Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol. 2014 Jun;15(7):757-66. Epub 2014 May 11. link to original article link to original protocol (in German) contains dosing details in manuscript PubMed NCT00785330

SMILE

SMILE: Steroid (Dexamethasone), Methotrexate, Ifosfamide, L-asparaginase, Etoposide

Regimen

Study	Dates of enrollment	Evidence
Yamaguchi et al. 2008	2005-2006	Phase 1
Kwong et al. 2012	2005-2012	Phase 2

Note: Asparaginase (Elspar) was discontinued by the manufacturer in December 2012, and is now essentially out of stock. Alternatives include Pegaspargase (Oncaspar) or Asparaginase Erwinia chrysanthemi (Erwinaze). Neither paper nor supplement specified the length of each cycle, but other SMILE regimens, e.g. Yamaguchi et al. 2008, describe 28-day cycles.

Glucocorticoid therapy

Dexamethasone (Decadron) 40 mg PO once per day on days 2 to 4

Chemotherapy

Methotrexate (MTX) 2000 mg/m² IV over 6 hours once on day 1
Ifosfamide (Ifex) 1500 mg/m² IV over 6 hours once per day on days 2 to 4, given with mesna
Asparaginase (Elspar) 6000 units/m² IV over 2 hours once per day on days 8, 10, 12, 14, 16, 18, 20
- Skin test done for asparaginase before each dose; Asparaginase Erwinia chrysanthemi used for patients who developed sensitivity to L-asparaginase from E. coli
Etoposide (Vepesid) 100 mg/m² IV over 2 hours once per day on days 2 to 4

Supportive therapy

Leucovorin (Folinic acid) 45 mg PO every 6 hours on days 2 to 4 (or until serum methotrexate level is below the toxic range), starting 24 hours after completion of methotrexate
- Methotrexate levels checked at 24, 48, and 72 hours after methotrexate is given, or until methotrexate levels fall below toxic range. Folinic acid should be continued until methotrexate levels are below toxic range.
Mesna (Mesnex) 900 mg/m² IV over 6 hours once per day on days 2 to 4, given with ifosfamide
Hydration with normal saline (no volume specified) every 8 hours on the day prior to methotrexate
Patients told to drink at least 2 liters of fluid per day on days 1 to 4; target urine output of greater than or equal to 3 liters per day on days 1 to 4
Filgrastim (Neupogen) 300 mcg SC once per day, starting on day 6, given until ANC greater than 1000/μL
Cotrimoxazole or Pentamidine (Nebupent) for PJP prophylaxis
Famotidine (Pepcid) and potassium slow release tablets (no dose specified) "for Dexamethasone (Decadron)" on days 2 to 4
Chlorpheniramine (Chlor-Trimeton) 10 mg PO once per day on days 8, 10, 12, 14, 16, 18, 20, prior to asparaginase
Hydrocortisone (Cortef) 100 mg IV once per day on days 8, 10, 12, 14, 16, 18, 20, prior to asparaginase

28-day cycle for up to 6 cycles (see note)

References

Phase 1: Yamaguchi M, Suzuki R, Kwong YL, Kim WS, Hasegawa Y, Izutsu K, Suzumiya J, Okamura T, Nakamura S, Kawa K, Oshimi K. Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia. Cancer Sci. 2008 May;99(5):1016-20. Epub 2008 Feb 19. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
Kwong YL, Kim WS, Lim ST, Kim SJ, Tang T, Tse E, Leung AY, Chim CS; Asia Lymphoma Study Group. SMILE for natural killer/T-cell lymphoma: analysis of safety and efficacy from the Asia Lymphoma Study Group. Blood. 2012 Oct 11;120(15):2973-80. Epub 2012 Aug 23. link to original article supplemental materials contains dosing details in supplement PubMed

NK- and T-cell lymphoma

Guidelines

ESMO

NCCN

Untreated

DDGP

Regimen

Glucocorticoid therapy

Chemotherapy

References

SMILE

Regimen

Glucocorticoid therapy

Chemotherapy

Supportive therapy

References

Relapsed or refractory

AspaMetDex

Regimen

Chemotherapy

Glucocorticoid therapy

Supportive therapy

Subsequent treatment

References

AspaMetDex (Erwinaze)

Regimen

Chemotherapy

Glucocorticoid therapy

Supportive therapy

Subsequent treatment

References

Fludarabine, Busulfan, Cyclophosphamide, then allo HSCT

Regimen variant #1, oral

Chemotherapy

Immunotherapy

GVHD prophylaxis

Regimen variant #2, intravenous

Chemotherapy

Immunotherapy

GVHD prophylaxis

References

SMILE

Regimen

Glucocorticoid therapy

Chemotherapy

Supportive therapy

References

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