NK- and T-cell lymphoma

Section editor
	Bhagirathbhai Dholaria, MBBS Vanderbilt University Nashville, TN

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

ESMO

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

"How I Treat"

• 2013: 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

DDGP

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Li et al. 2016 (CTTNKTL-Ⅲ/Ⅳ)	2011-2014	Phase IV (E-switch-ic)	SMILE	Seems to have superior OS OS24: 74% vs 45%

Note: dosing information is from the NCT record.

Chemotherapy

• Dexamethasone (Decadron) 15 mg/m² IV once per day on days 1 to 5
• 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 at least 3 cycles

References

1. 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 protocol PubMed NCT01501149

SMILE

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kwong et al. 2012	2005-2012	Phase II
Li et al. 2016 (CTTNKTL-Ⅲ/Ⅳ)	2011-2014	Phase IV (E-switch-ic)	DDGP	Seems to have inferior OS

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. 2011, describe 28-day cycles.

Chemotherapy

• Dexamethasone (Decadron) 40 mg 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 over 6 hours once per day on days 2 to 4, given with Mesna (Mesnex)
• 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 medications

• Folinic acid (Leucovorin) 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 (MTX)
  • 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 (Ifex)
• Hydration with normal saline (no volume specified) every 8 hours on the day prior to Methotrexate (MTX)
• 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/uL
• 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 (Elspar)
• Hydrocortisone (Cortef) 100 mg IV once per day on days 8, 10, 12, 14, 16, 18, 20, prior to Asparaginase (Elspar)

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

References

1. 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 supplemental materials contain verified protocol PubMed
2. 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

Relapsed or refractory

FluBuCy, then allo HSCT

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FluBuCy: Fludarabine, Busulfan, Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence
Glass et al. 2014 (DSHNHL R3)	2004-2009	Phase II

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

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. 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 verified protocol PubMed NCT00785330

Pembrolizumab monotherapy

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Regimen

Study	Evidence
Kwong et al. 2017	Case series

Note: prospective trials are underway.

Immunotherapy

• Pembrolizumab (Keytruda) 2 mg/kg IV once on day 1

21-day cycles

References

1. Kwong YL, Chan TSY, Tan D, Kim SJ, Poon LM, Mow B, Khong PL, Loong F, Au-Yeung R, Iqbal J, Phipps C, Tse E. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood. 2017 Apr 27;129(17):2437-2442. Epub 2017 Feb 10. link to original article PubMed

SMILE

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

Regimen

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

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.

Chemotherapy

• Dexamethasone (Decadron) 40 mg 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 over 6 hours once per day on days 2 to 4, given with Mesna (Mesnex)
• 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 medications

• Folinic acid (Leucovorin) 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 (MTX)
  • 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 (Ifex)
• Hydration with normal saline (no volume specified) every 8 hours on the day prior to Methotrexate (MTX)
• 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/uL
• 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 (Elspar)
• Hydrocortisone (Cortef) 100 mg IV once per day on days 8, 10, 12, 14, 16, 18, 20, prior to Asparaginase (Elspar)

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

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. 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 supplemental materials contain verified protocol PubMed