NK- and T-cell lymphoma

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Bhagirathbhai Dholaria, MBBS
Vanderbilt University
Nashville, TN

Note: The most common subtype of this condition (ENKTCL, nasal type) has a dedicated page.

6 regimens on this page
6 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

"How I Treat"

NCCN

Untreated

DDGP

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 4 (E-switch-ic) SMILE Seems to have superior OS
OS24: 74% vs 45%

Note: dosing information is from the NCT record.

Glucocorticoid therapy

Chemotherapy

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 dosing details PubMed NCT01501149

SMILE

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

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kwong et al. 2012 2005-2012 Phase 2
Li et al. 2016 (CTTNKTL-III/IV) 2011-2014 Phase 4 (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.

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

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 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

Relapsed or refractory

AspaMetDex

AspaMetDex: Asparaginase, Methotrexate, Dexamethasone

Regimen

Study Evidence Efficacy
Jaccard et al. 2011 (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:
    • 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

Glucocorticoid therapy

  • Dexamethasone (Decadron) by the following age-based criteria:
    • 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 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. link to original article contains dosing details in manuscript PubMed NCT00283985

AspaMetDex (Erwinaze)

AspaMetDex: Asparaginase, Methotrexate, Dexamethasone

Regimen

Study Evidence Efficacy
Jaccard et al. 2011 (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:
    • 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 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. link to original article contains dosing details in manuscript PubMed NCT00283985

FluBuCy, then allo HSCT

FluBuCy: Fludarabine, Busulfan, Cyclophosphamide

Regimen

Study Years of enrollment Evidence
Glass et al. 2014 (DSHNHL R3) 2004-2009 Phase 2

Chemotherapy

Immunosuppressive therapy

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

Pembrolizumab monotherapy

Regimen

Study Evidence
Kwong et al. 2017 Case series

Note: prospective trials are underway.

Immunotherapy

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

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 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

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