NK- and T-cell lymphoma

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Bhagirathbhai Dholaria, MBBS
Vanderbilt University
Nashville, TN, USA

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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

NCCN

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

Chemotherapy

21-day cycle for 6 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 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

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

  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 contains dosing details in supplement 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
    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

21-day cycle for 3 cycles

Subsequent treatment

  • See paper for details about further treatment

References

  1. 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

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

21-day cycle for 3 cycles

Subsequent treatment

  • See paper for details about further treatment

References

  1. 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

Immunotherapy

GVHD prophylaxis


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

Immunotherapy

GVHD prophylaxis

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 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

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

  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 dosing details in manuscript 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 contains dosing details in supplement PubMed