Extranodal NK- and T-cell lymphoma, nasal type

Section editor
	Bhagirathbhai Dholaria, MBBS Vanderbilt University Nashville, TN

10 regimens on this page 10 variants on this page

Guidelines

ESMO

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

"How I Treat"

• Tse E, Kwong YL. How I treat NK/T-cell lymphomas. Blood. 2013 Jun 20;121(25):4997-5005. Epub 2013 May 7. link to original article PubMed

NCCN

• NCCN Guidelines - T-cell Lymphomas

Untreated

Cisplatin & RT

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Cisplatin & RT: Cisplatin & Radiation Therapy

Regimen

Study	Evidence	Efficacy
Kim et al. 2009a	Phase II	ORR: 83%

Chemotherapy

• Cisplatin (Platinol) 30 mg/m² IV once per day on days 1, 8, 15, 22

Radiotherapy

• Concurrent radiation therapy to the primary tumor, 1.8 to 2 Gy fractions (median total dose: 40 Gy), given 5 times per week.

4-week course

Subsequent treatment

• VIPD consolidation, 3 to 5 weeks after the last dose of cisplatin

References

1. Kim SJ, Kim K, Kim BS, Kim CY, Suh C, Huh J, Lee SW, Kim JS, Cho J, Lee GW, Kang KM, Eom HS, Pyo HR, Ahn YC, Ko YH, Kim WS. Phase II trial of concurrent radiation and weekly cisplatin followed by VIPD chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-Cell Lymphoma: Consortium for Improving Survival of Lymphoma study. J Clin Oncol. 2009 Dec 10;27(35):6027-32. link to original article contains verified protocol PubMed

DEP & RT

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DEP & RT: Dexamethasone, Etoposide, Platinol (Cisplatin), Radiation Therapy

Regimen

Study	Evidence	Efficacy
Tsai et al. 2014	Phase II	ORR: 81%

Dosing details not available in the abstract.

Chemotherapy

• Dexamethasone (Decadron)
• Etoposide (Vepesid)
• Cisplatin (Platinol)

28-day cycle for 2 cycles

Radiotherapy

• Concurrent radiation therapy to the primary tumor, 50.4 Gy in 28 fractions

5.5-week course

Subsequent treatment

• VIPD consolidation

References

1. Tsai HJ, Lin SF, Chen CC, Chen TY, Su WC, Hwang WL, Lin JC, Chiou TJ, Kao WY, Chiu CF, Chang YF, Chang JS, Chang MC, Su IJ. Long-term results of a phase II trial with frontline concurrent chemoradiotherapy followed by consolidation chemotherapy for localized nasal natural killer/T-cell lymphoma. Eur J Haematol. 2015 Feb;94(2):130-7. Epub 2014 Oct 10. link to original article PubMed

DeVIC & RT

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DeVIC & RT: Dexamethasone, VP-16 (Etoposide), Ifosfamide, Carboplatin, Radiation Therapy

Regimen

Study	Evidence	Efficacy
Yamaguchi et al. 2009 (JCOG0211)	Phase II	ORR: 81%

Chemotherapy, Dose Level I

• Dexamethasone (Decadron) 40 mg IV once per day on days 1 to 3
• Etoposide (Vepesid) 67 mg/m² IV over 2 hours once per day on days 1 to 3
• Ifosfamide (Ifex) 1000 mg/m² IV over 3 hours once per day on days 1 to 3
• Carboplatin (Paraplatin) 200 mg/m² IV over 30 minutes once on day 1

Chemotherapy, Dose Level II

• Dexamethasone (Decadron) 40 mg IV once per day on days 1 to 3
• Etoposide (Vepesid) 100 mg/m² IV over 2 hours once per day on days 1 to 3
• Ifosfamide (Ifex) 1500 mg/m² IV over 3 hours once per day on days 1 to 3
• Carboplatin (Paraplatin) 300 mg/m² IV over 30 minutes once on day 1

Supportive medications

• Filgrastim (Neupogen) (dose/route/schedule not specified) started for WBC count less than 2 x 10⁹/L or ANC less than 1000/uL; discontinued if WBC count greater than 5 x 10⁹/L.

21-day cycle for 3 cycles

Radiotherapy

Started simultaneously with the beginning of cycle 1 of chemotherapy

• Concurrent radiation therapy as follows:
  • Stage IE disease: 2 Gy fractions x 25 fractions (total dose: 50 Gy)
  • Stage IIE disease: 1.8 Gy fractions x 28 fractions (total dose: 50.4 Gy)

5- to 6-week course

References

1. Yamaguchi M, Tobinai K, Oguchi M, Ishizuka N, Kobayashi Y, Isobe Y, Ishizawa K, Maseki N, Itoh K, Usui N, Wasada I, Kinoshita T, Ohshima K, Matsuno Y, Terauchi T, Nawano S, Ishikura S, Kagami Y, Hotta T, Oshimi K. Phase I/II study of concurrent chemoradiotherapy for localized nasal natural killer/T-cell lymphoma: Japan Clinical Oncology Group Study JCOG0211. J Clin Oncol. 2009 Nov 20;27(33):5594-600. link to original article contains verified protocol PubMed
   1. Update: Yamaguchi M, Tobinai K, Oguchi M, Ishizuka N, Kobayashi Y, Isobe Y, Ishizawa K, Maseki N, Itoh K, Usui N, Wasada I, Kinoshita T, Hotta T, Tsukasaki K, Oshimi K. Concurrent chemoradiotherapy for localized nasal natural killer/T-cell lymphoma: an updated analysis of the Japan clinical oncology group study JCOG0211. J Clin Oncol. 2012 Nov 10;30(32):4044-6. Epub 2012 Oct 8. link to original article PubMed

GELOX/RT

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GELOX/RT: Gemcitabine, L-asparaginase, Oxaliplatin, alternating with Radiation Therapy

Protocol

Study	Evidence	Efficacy
Wang et al. 2012	Phase II	ORR: 96%

Note: total number of chemotherapy cycles was limited to 6.

Chemotherapy, part 1

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Asparaginase (Elspar) 6000 units/m² IV once per day on days 1 to 7
• Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

21-day cycle for at least 2 cycles, followed by:

Radiotherapy

• IFRT to 56 Gy in 28 fractions, 5 fractions per week

5.5-week course, followed within one week by:

Chemotherapy, part 2

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Asparaginase (Elspar) 6000 units/m² IV once per day on days 1 to 7
• Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

21-day cycle for up to 4 cycles

References

1. Wang L, Wang ZH, Chen XQ, Li YJ, Wang KF, Xia YF, Xia ZJ. First-line combination of gemcitabine, oxaliplatin, and L-asparaginase (GELOX) followed by involved-field radiation therapy for patients with stage IE/IIE extranodal natural killer/T-cell lymphoma. Cancer. 2013 Jan 15;119(2):348-55. Epub 2012 Jul 18. link to original article contains verified protocol PubMed

LVP "Sandwich"

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LVP: L-asparaginase, Vincristine, Prednisolone

Protocol

Study	Evidence	Efficacy
Jiang et al. 2011	Phase II	ORR: 84%

Chemotherapy, part 1

• Asparaginase (Elspar) 6000 units/m² IV once per day on days 1 to 5
• Vincristine (Oncovin) 1.4 mg/m² IV once on day 1
• Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5

21-day cycle for 2 cycles, followed by:

Radiotherapy

• External beam radiotherapy to the nasal cavity and surrounding sinuses, 56 Gy in 28 fractions, once per day, five days per week

5.5-week course, followed in one week by:

Chemotherapy, part 2

• Asparaginase (Elspar) 6000 units/m² IV once per day on days 1 to 5
• Vincristine (Oncovin) 1.4 mg/m² IV once on day 1
• Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5

21-day cycle for up to 4 cycles

References

1. Jiang M, Zhang H, Jiang Y, Yang Q, Xie L, Liu W, Zhang W, Ji X, Li P, Chen N, Zhao S, Wang F, Zou L. Phase 2 trial of "sandwich" L-asparaginase, vincristine, and prednisone chemotherapy with radiotherapy in newly diagnosed, stage IE to IIE, nasal type, extranodal natural killer/T-cell lymphoma. Cancer. 2012 Jul 1;118(13):3294-301. Epub 2011 Dec 2. link to original article contains verified protocol PubMed

MESA/RT

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MESA/RT: Methotrexate, Etoposide, Steroid (dexamethasone), PEG-A-sparaginase alternating with Radiation Ttherapy

Protocol

Study	Evidence	Efficacy
Liang et al. 2016	Phase II	ORR: 87%

Note: this regimen also incorporates radiation, see text for details.

Chemotherapy, part 1

• Methotrexate (MTX) 2000 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 2 to 4
• Dexamethasone (Decadron) 20 mg/m² IV once per day on days 2 to 5
• Pegaspargase (Oncaspar) 2500 IU/m² IM once on day 5

21-day cycle for at least 3 cycles, followed by:

Radiotherapy

• Radiation therapy, 45 to 50 Gy in 25 fractions

One course, followed by:

Chemotherapy, part 2

• Methotrexate (MTX) 2000 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 2 to 4
• Dexamethasone (Decadron) 20 mg/m² IV once per day on days 2 to 5
• Pegaspargase (Oncaspar) 2500 IU/m² IM once on day 5

21-day cycle for a maximum of 7 cycles

References

1. Liang R, Gao GX, Chen JP, Wang JS, Wang XM, Zeng Y, Bai QX, Zhang T, Yang L, Dong BX, Gu HT, Shu MM, Hao CX, Wang JH, Zhang N, Chen XQ. A phase 2 study of methotrexate, etoposide, dexamethasone, and pegaspargase chemotherapy for newly diagnosed, relapsed, or refractory extranodal natural killer/T-cell lymphoma, nasal type: a multicenter trial in Northwest China. Hematol Oncol. 2017 Dec;35(4):619-629. Epub 2016 Oct 10. link to original article link to PMC article contains verified protocol PubMed

SMILE

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

Regimen

Study	Evidence	Efficacy
Yamaguchi et al. 2011	Phase II	ORR: 79%

Chemotherapy

• Dexamethasone (Decadron) 40 mg IV or PO once per day on days 2 to 4
• Methotrexate (MTX) 2000 mg/m² IV over 6 hours once on day 1
• Ifosfamide (Ifex) 1500 mg/m² IV once per day on days 2 to 4
• Asparaginase (Elspar) 6000 units/m² IV once per day on days 8, 10, 12, 14, 16, 18, 20
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 2 to 4

Supportive medications

• Folinic acid (Leucovorin) 15 mg IV or PO every 6 hours on days 2 to 4, beginning 30 hours after completion of Methotrexate (MTX)
• Mesna (Mesnex) 300 mg/m² IV three times per day on days 2 to 4; first dose given together with Ifosfamide (Ifex), second dose given at 4 hours after start of Ifosfamide (Ifex), and third dose given 8 hours after start of Ifosfamide (Ifex)
• Filgrastim (Neupogen) (dose not specified) IV or SC once per day, starting on day 6, given until WBC count greater than 5 x 10⁹/L
• Trimethoprim-Sulfamethoxazole (Bactrim DS) prophylaxis recommended

28-day cycle for 2 cycles

After 2 cycles, patients could receive additional treatment with SMILE and/or other chemotherapy, with or without autologous/allogeneic stem cell transplant.

References

1. 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 verified protocol PubMed content property of HemOnc.org
2. Yamaguchi M, Kwong YL, Kim WS, Maeda Y, Hashimoto C, Suh C, Izutsu K, Ishida F, Isobe Y, Sueoka E, Suzumiya J, Kodama T, Kimura H, Hyo R, Nakamura S, Oshimi K, Suzuki R. 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. J Clin Oncol. 2011 Nov 20;29(33):4410-6. Epub 2011 Oct 11. link to original article contains verified protocol PubMed

Consolidation after upfront therapy

VIPD

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VIPD: VP-16 (Etoposide), Ifosfamide, Platinol (Cisplatin), Dexamethasone

Regimen

Study	Evidence
Kim et al. 2009a	Phase II
Tsai et al. 2014	Phase II

Details here are from the Kim et al. 2009a manuscript.

Preceding treatment

• Kim et al. 2009a: Cisplatin & concurrent RT
• Tsai et al. 2014: DEP & concurrent RT

Chemotherapy

• Etoposide (Vepesid) 100 mg/m² IV over 90 minutes once per day on days 1 to 3
• Ifosfamide (Ifex) 1200 mg/m² IV over 60 minutes once per day on days 1 to 3
• Cisplatin (Platinol) 33 mg/m² IV over 60 minutes once per day on days 1 to 3
• Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4

Supportive medications

• Mesna (Mesnex) 240 mg/m² IV over 15 minutes once per day on days 1 to 3
• G-CSF given for grade 3 or 4 neutropenia

21-day cycle for up to 3 cycles

References

1. Kim SJ, Kim K, Kim BS, Kim CY, Suh C, Huh J, Lee SW, Kim JS, Cho J, Lee GW, Kang KM, Eom HS, Pyo HR, Ahn YC, Ko YH, Kim WS. Phase II trial of concurrent radiation and weekly cisplatin followed by VIPD chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-Cell Lymphoma: Consortium for Improving Survival of Lymphoma study. J Clin Oncol. 2009 Dec 10;27(35):6027-32. link to original article contains verified protocol PubMed
2. Tsai HJ, Lin SF, Chen CC, Chen TY, Su WC, Hwang WL, Lin JC, Chiou TJ, Kao WY, Chiu CF, Chang YF, Chang JS, Chang MC, Su IJ. Long-term results of a phase II trial with frontline concurrent chemoradiotherapy followed by consolidation chemotherapy for localized nasal natural killer/T-cell lymphoma. Eur J Haematol. 2015 Feb;94(2):130-7. Epub 2014 Oct 10. link to original article PubMed

Relapsed or refractory

AspaMetDex

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AspaMetDex: Asparaginase, Methotrexate, Dexamethasone

Regimen

Study	Evidence	Efficacy
Jaccard et al. 2011	Phase II	ORR: 78%

Chemotherapy

• Asparaginase (Elspar) 6000 units/m² IM once per day on days 2, 4, 6, 8
• Methotrexate (MTX) as follows:
  • Age up to 70: 3000 mg/m² (route not specified) once on day 1
  • Older than 70: 2000 mg/m² (route not specified) once on day 1
• Dexamethasone (Decadron) as follows:
  • Age up to 70: 40 mg PO once per day on days 1 to 4
  • Older than 70: 20 mg PO once per day on days 1 to 4

Supportive medications

• Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose/route/schedule not specified) prophylaxis, discontinued during Methotrexate (MTX) administration
• Valacyclovir (Valtrex) (dose/route/schedule not specified) prophylaxis
• For Methotrexate (MTX): alkaline hydration and Folinic acid (Leucovorin) rescue (dose/route/schedule not specified)

21-day cycle for 3 cycles

Subsequent treatment

• See paper for details about further treatment

References

1. 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 and GOELAMS Intergroup. 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. link to original article contains verified protocol PubMed

AspaMetDex (Erwinaze)

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AspaMetDex: Asparaginase, Methotrexate, Dexamethasone

Regimen

Study	Evidence	Efficacy
Jaccard et al. 2011	Phase II	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) as follows:
  • Age up to 70: 3000 mg/m² (route not specified) once on day 1
  • Older than 70: 2000 mg/m² (route not specified) once on day 1
• Dexamethasone (Decadron) as follows:
  • Age up to 70: 40 mg PO once per day on days 1 to 4
  • Older than 70: 20 mg PO once per day on days 1 to 4

Supportive medications

• Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose/route/schedule not specified) prophylaxis, discontinued during Methotrexate (MTX) administration
• Valacyclovir (Valtrex) (dose/route/schedule not specified) prophylaxis
• For Methotrexate (MTX): alkaline hydration and Folinic acid (Leucovorin) rescue (dose/route/schedule not specified)

21-day cycle for 3 cycles

Subsequent treatment

• See paper for details about further treatment

References

1. 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 and GOELAMS Intergroup. 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. link to original article contains verified protocol PubMed

L-Asparaginase, Vincristine, Prednisolone

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LVP: L-asparaginase, Vincristine, Prednisolone

Regimen

Study	Evidence	Efficacy
Yong et al. 2003	Phase II, <20 patients	ORR: 83%

Regimen details are from a review article; original article is not available through PubMed

Chemotherapy

• Asparaginase (Elspar) 6000 units/m² IV once per day on days 1 to 5
• Vincristine (Oncovin) 1.4 mg/m² IV once on day 1
• Prednisolone (Millipred) 100 mg PO once per day on days to 5

References

1. Yong W, Zheng W, Zhang Y, Zhu J, Wei Y, Zhu D, Li J. L-asparaginase-based regimen in the treatment of refractory midline nasal/nasal-type T/NK-cell lymphoma. Int J Hematol. 2003 Aug;78(2):163-7. PubMed

SMILE

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

Regimen

Study	Evidence	Efficacy
Yamaguchi et al. 2011	Phase II	ORR: 79%

Chemotherapy

• Dexamethasone (Decadron) 40 mg IV or PO once per day on days 2 to 4
• Methotrexate (MTX) 2000 mg/m² IV over 6 hours once on day 1
• Ifosfamide (Ifex) 1500 mg/m² IV once per day on days 2 to 4
• Asparaginase (Elspar) 6000 units/m² IV once per day on days 8, 10, 12, 14, 16, 18, 20
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 2 to 4

Supportive medications

• Folinic acid (Leucovorin) 15 mg IV or PO every 6 hours on days 2 to 4, beginning 30 hours after completion of Methotrexate (MTX)
• Mesna (Mesnex) 300 mg/m² IV three times per day on days 2 to 4; first dose given together with Ifosfamide (Ifex), second dose given at 4 hours after start of Ifosfamide (Ifex), and third dose given 8 hours after start of Ifosfamide (Ifex)
• Filgrastim (Neupogen) (dose not specified) IV or SC once per day, starting on day 6, given until WBC count greater than 5 x 10⁹/L
• Trimethoprim-Sulfamethoxazole (Bactrim DS) prophylaxis recommended

28-day cycle for 2 cycles

After 2 cycles, patients could receive additional treatment with SMILE and/or other chemotherapy, with or without autologous/allogeneic stem cell transplant.

References

1. 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 verified protocol PubMed content property of HemOnc.org
2. Yamaguchi M, Kwong YL, Kim WS, Maeda Y, Hashimoto C, Suh C, Izutsu K, Ishida F, Isobe Y, Sueoka E, Suzumiya J, Kodama T, Kimura H, Hyo R, Nakamura S, Oshimi K, Suzuki R. 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. J Clin Oncol. 2011 Nov 20;29(33):4410-6. Epub 2011 Oct 11. link to original article contains verified protocol PubMed