NK- and T-cell lymphoma

Carboplatin & Paclitaxel (CP)

CP: Carboplatin & Paclitaxel

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (C)	1a. CP & Nivolumab 1b. CVb & Nivolumab 1c. DC & Nivolumab	Inferior EFS

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details. This study was conducted in the United States. The reason for the study was that an unanswered question at the time was whether adding an immune checkpoint inhibitor would improve outcomes.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 or 6 IV once on day 1
• Paclitaxel (Taxol) 175 or 200 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

References

1. CheckMate 816: Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, Kerr K, Wang C, Ciuleanu TE, Saylors GB, Tanaka F, Ito H, Chen KN, Liberman M, Vokes EE, Taube JM, Dorange C, Cai J, Fiore J, Jarkowski A, Balli D, Sausen M, Pandya D, Calvet CY, Girard N; CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. Epub 2022 Apr 11. link to original article contains dosing details in manuscript PubMed NCT02998528

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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

"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

All lines of therapy

DDGP

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

Regimen

Study	Evidence	Comparator	Efficacy
Li et al. 2016	Phase III	SMILE	Seems to have superior OS

Note: drug names but no further details were provided in the abstract; 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. 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

SMILE

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

Regimen

Study	Evidence	Comparator	Efficacy
Kwong et al. 2012	Phase II
Li et al. 2016	Phase III	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).

Chemotherapy

• Dexamethasone (Decadron) 40 mg PO once per day on days 2 to 4
• Methotrexate (MTX) 2000 mg/m² in 500 mL normal saline IV over 6 hours once on day 1
• Ifosfamide (Ifex) 1500 mg/m² in 1 liter normal saline IV over 6 hours once per day on days 2 to 4, given together with Mesna (Mesnex)
• Asparaginase (Elspar) 6000 units/m² in 250 mL normal saline 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 (Erwinaze) used for patients who developed sensitivity to L-asparaginase from E. coli
• Etoposide (Vepesid) 100 mg/m² in 500 mL normal saline IV over 2 hours once per day on days 2 to 4

Supportive medications

• Folinic acid (Leucovorin) 45 mg PO Q6H x 4 doses per day 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 together with Ifosfamide (Ifex)
• Hydration with normal saline (no volume specified) Q8H x 1 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 prior to Asparaginase (Elspar) infusions on days 8, 10, 12, 14, 16, 18, 20
• Hydrocortisone (Cortef) 100 mg IV once prior to Asparaginase (Elspar) infusions on days 8, 10, 12, 14, 16, 18, 20

Given for up to 6 cycles

Neither paper nor supplement specified the length of each cycle, but other SMILE regimens, e.g. Yamaguchi et al. 2011, describe 28-day cycles.

References

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. 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
3. 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