T-cell lymphoma

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Anaplastic large-cell lymphoma (ALCL)

Relapsed/refractory

Brentuximab vedotin (Adcetris)

Regimen, Pro et al. 2012

Phase II

• Brentuximab vedotin (Adcetris) 1.8 mg/kg IV over 30 minutes on day 1

3-week cycles up to 16 infusions

References

1. Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, Matous J, Ramchandren R, Fanale M, Connors JM, Yang Y, Sievers EL, Kennedy DA, Shustov A. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012 Jun 20;30(18):2190-6. Epub 2012 May 21. link to original article contains verified protocol PubMed

Cutaneous T-cell Lymphoma (CTCL)

Relapsed/refractory

Belinostat (Beleodaq)

Regimen, Pohlman et al. 2009

Phase II

• Belinostat (Beleodaq) 1000 mg/m2 IV over 30 minutes once per day on days 1 to 5

3-week cycles

References

1. Abstract: Pohlman, Brad, Advani, Ranjana, Duvic, Madeleine, Hymes, Kenneth B., Intragumtornchai, Tanin, Lekhakula, Arnuparp, Shpilberg, Ofer, Lerner, Adam, Ben-Yehuda, Dina, beylot-Barry, Marie, Hillen, Uwe, Fagerberg, Jan, Foss, Francine M. Final Results of a Phase II Trial of Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma. ASH Annual Meeting Abstracts 2009 114: 920. link to abstract

Bendamustine (Treanda)

Regimen, Demaj et al. 2013 (BENTLY)

Phase II

• Bendamustine (Treanda) 120 mg/m2 IV once per day over 30 to 60 minutes on days 1 & 2

3-week cycles x 6 cycles

References

1. Damaj G, Gressin R, Bouabdallah K, Cartron G, Choufi B, Gyan E, Banos A, Jaccard A, Park S, Tournilhac O, Schiano-de Collela JM, Voillat L, Joly B, Le Gouill S, Saad A, Cony-Makhoul P, Vilque JP, Sanhes L, Schmidt-Tanguy A, Bubenheim M, Houot R, Diouf M, Marolleau JP, Béné MC, Martin A, Lamy T. Results from a prospective, open-label, phase II trial of bendamustine in refractory or relapsed T-cell lymphomas: the BENTLY trial. J Clin Oncol. 2013 Jan 1;31(1):104-10. Epub 2012 Oct 29. link to original article contains verified protocol PubMed

Bexarotene (Targretin)

Regimen, Duvic et al. 2001

Phase II

This dose is considered the optimal starting dose by Duvic et al.

• Bexarotene (Targretin) 300 mg/m2 PO once per day

Duration not specified; presumptively until progression or intolerance

References

1. Duvic M, Hymes K, Heald P, Breneman D, Martin AG, Myskowski P, Crowley C, Yocum RC; Bexarotene Worldwide Study Group. Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol. 2001 May 1;19(9):2456-71. link to original article contains verified protocol PubMed
2. Duvic M, Martin AG, Kim Y, Olsen E, Wood GS, Crowley CA, Yocum RC; Worldwide Bexarotene Study Group. Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol. 2001 May;137(5):581-93. link to original article contains verified protocol PubMed

Brentuximab vedotin (Adcetris)

Regimen, Krathen et al. 2012

Pilot, <20 patients reported

• Brentuximab vedotin (Adcetris) 1.8 mg/kg IV over 30 minutes on day 1

3-week cycles up to 16 infusions

References

1. Abstract: Michael Krathen, MD, Uma Sundram, MD, PhD, Sameer Bashey, MD, Katherine Sutherland, C-PA, Katrin Salva, MD, Gary S Wood, MD, Ranjana H. Advani, MD, Richard T. Hoppe, MD, Sunil Reddy, MD, Randall Armstrong, Seema Nagpal, MD, Melissa Pulitzer, MD, Steven M. Horwitz, MD and Youn H. Kim, MD. Brentuximab Vedotin Demonstrates Significant Clinical Activity in Relapsed or Refractory Mycosis Fungoides with Variable CD30 Expression. ASH 2012 abstract 797 link to abstract contains verified protocol

Denileukin Diftitox (Ontak)

Regimen, Olsen et al. 2001 & Prince et al. 2010

Phase III

Dose is that which was recommended by Prince et al. 2010 based on superior response.

• Denileukin diftitox (Ontak) 18 mcg/kg IV over 30 to 60 minutes once per day on days 1 to 5
  • Olsen et al. 2001 & Prince et al. 2010 also investigated Denileukin diftitox (Ontak) 9 mcg/kg IV once per day on days 1 to 5. Olsen et al. 2001's Denileukin diftitox (Ontak) was given over 15 to 60 minutes.

Supportive medications:

• "Premedication with Acetaminophen (Tylenol) [≤ 650 mg in Olsen et al. 2001] and an antihistamine was required 30 to 60 minutes before each infusion" and could be used after infusions as needed.
• Olsen et al. 2001 used Promethazine (Phenergan) 25 mg or Prochlorperazine (Compazine) 10 mg (route/schedule not specified) as needed for nausea.
• Corticosteroid use was not allowed.

21-day cycles x up to 8 cycles; up to 3 additional cycles allowed in the Olsen et al. 2001 trial for patients who had ongoing response

References

1. Olsen E, Duvic M, Frankel A, Kim Y, Martin A, Vonderheid E, Jegasothy B, Wood G, Gordon M, Heald P, Oseroff A, Pinter-Brown L, Bowen G, Kuzel T, Fivenson D, Foss F, Glode M, Molina A, Knobler E, Stewart S, Cooper K, Stevens S, Craig F, Reuben J, Bacha P, Nichols J. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol. 2001 Jan 15;19(2):376-88. link to original article contains verified protocol PubMed
2. Prince HM, Duvic M, Martin A, Sterry W, Assaf C, Sun Y, Straus D, Acosta M, Negro-Vilar A. Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2010 Apr 10;28(11):1870-7. Epub 2010 Mar 8. link to original article contains verified protocol PubMed
3. Duvic M, Martin AG, Olsen EA, Fivenson DP, Prince HM. Efficacy and safety of denileukin diftitox retreatment in patients with relapsed cutaneous T-cell lymphoma. Leuk Lymphoma. 2013 Mar;54(3):514-9. Epub 2012 Sep 3. link to original article PubMed
4. Meta-analysis: Duvic M, Geskin L, Prince HM. Duration of response in cutaneous T-cell lymphoma patients treated with denileukin diftitox: results from 3 phase III studies. Clin Lymphoma Myeloma Leuk. 2013 Aug;13(4):377-84. Epub 2013 Jun 14. link to original article PubMed

Lenalidomide (Revlimid)

Regimen

Phase II

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21, increased by 5 mg per day with each cycle to a maximum of 25 mg PO once per day, as tolerated

28-day cycles, up to 2 years or until disease progression

References

1. Querfeld C, Rosen ST, Guitart J, Duvic M, Kim YH, Dusza SW, Kuzel TM. Results of an open-label multicenter phase II trial of lenalidomide monotherapy in refractory mycosis fungoides and Sezary syndrome. Blood. 2014 Feb 20;123(8):1159-66. Epub 2013 Dec 11. link to original article contains verified protocol PubMed

Pralatrexate (Folotyn)

Regimen

Phase II

Dose is that identified as recommended based on de-escalation strategy.

• Pralatrexate (Folotyn) 15 mg/m2 IV push once per day on days 1, 8, 15

Supportive medications:

• Cyanocobalamin (Vitamin B12) 1 mg IM once every 8 to 10 weeks, within 10 weeks of treatment initiation
• Folic acid (Folate) 1 mg PO once per day, starting at least 10 days prior to treatment initiation

4-week cycles, given until progression of disease, unacceptable toxicity, or patient/physician preference

References

1. Horwitz SM, Kim YH, Foss F, Zain JM, Myskowski PL, Lechowicz MJ, Fisher DC, Shustov AR, Bartlett NL, Delioukina ML, Koutsoukos T, Saunders ME, O'Connor OA, Duvic M. Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood. 2012 May 3;119(18):4115-22. Epub 2012 Mar 6. link to original article contains verified protocol PubMed

Romidepsin (Istodax)

Phase II

Regimen, Whittaker et al. 2010

• Romidepsin (Istodax) 14 mg/m2 IV over 4 hours once per day on days 1, 8, 15

28-day cycles, up to 6 cycles, with optional extension of treatment for patients with stable disease or response

References

1. Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M, Scarisbrick J, Reddy S, Robak T, Becker JC, Samtsov A, McCulloch W, Kim YH. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol. 2010 Oct 10;28(29):4485-91. Epub 2010 Aug 9. link to original article contains verified protocol PubMed

Vorinostat (Zolinza)

Regimen, Olsen et al. 2007

Phase II

• Vorinostat (Zolinza) 400 mg PO once per day

Continued on drug until disease progression or intolerable toxicity

References

1. Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, Frankel SR, Chen C, Ricker JL, Arduino JM, Duvic M. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007 Jul 20;25(21):3109-15. link to original article contains verified protocol PubMed

Extranodal NK/T-cell lymphoma (ENKTCL), nasal type

Untreated

Cisplatin & Concurrent RT -> VIPD

VIPD: VP-16, Ifosfamide, Platinol, Dexamethasone

Regimen, Kim et al. 2009

Phase II

Chemoradiation

• Cisplatin (Platinol) 30 mg/m2 IV once per week
• Concurrent radiation therapy to the primary tumor, 1.8 to 2 Gy fractions (median total dose: 40 Gy), given 5 times per week.

Chemotherapy

Chemotherapy starts 3 to 5 weeks after the last dose of cisplatin

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

DeVIC & Concurrent RT

DeVIC: Dexamethasone, VP-16, Ifosfamide, Carboplatin

Regimen, Yamaguchi et al. 2009 (JCOG0211)

Phase II

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

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 leukocyte count <2,000/μL or ANC <1,000/μL; discontinued if leukocyte count >5,000/μL.

21-day cycles x 3 cycles

Concurrent radiation therapy

Started simultaneously with the beginning of cycle 1 of chemotherapy

• Stage IE disease: Concurrent radiation therapy, 2 Gy fractions x 25 fractions (total dose: 50 Gy) over 5 weeks
• Stage IIE disease: Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions (total dose: 50.4 Gy) over 6 weeks

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
2. 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

GELOX: Gemcitabine, L-asparaginase, Oxaliplatin

Regimen

Phase II

• 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 once on day 1

3-weeks cycles for at least 2 cycles, then:

• Involved field radiation to 56 grays (Gy) in 28 fractions, 5 fractions per week

Followed by more chemotherapy within one week of radiation completion, up to 6 total 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"

LVP: L-asparaginase, Vincristine, Prednisolone

Regimen

Phase II

• 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

3-week cycles x 2 cycles, then

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

Resume chemotherapy one week after completion of radiation, up to 6 total 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

SMILE

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

Regimen

Phase II

• Dexamethasone (Decadron) 40 mg PO/IV 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 PO/IV Q6H x 4 doses per day 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) SC/IV once per day starting on day 6, given until WBC >5 x 10⁹/L
• Trimethoprim/Sulfamethoxazole (Bactrim DS) prophylaxis recommended

28-day cycles x 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. 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

Relapsed/refractory

AspaMetDex

AspaMetDex: Asparaginase, Methotrexate, Dexamethasone

Regimen, Jaccard et al. 2011

Phase II

• Asparaginase (Elspar) 6000 units/m2 IM once per day on days 2, 4, 6, 8
  • Patients who had allergies to Asparaginase (Elspar) received Asparaginase Erwinia chrysanthemi (Erwinaze) 20,000 units/m2 IM once per day on days 2, 4, 6, 8
• Methotrexate (MTX) 3000 mg/m2 (route not specified) once on day 1
  • Patients >70 years old received Methotrexate (MTX) 2000 mg/m2 (route not specified) once on day 1
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
  • Patients >70 years old received Dexamethasone (Decadron) 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 cycles x 3 cycles; see Jaccard et al. 2011 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

LVP

LVP: L-asparaginase, Vincristine, Prednisolone

Regimen

Phase II, <20 patients reported

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

• 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

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

Regimen

Phase II

• Dexamethasone (Decadron) 40 mg PO/IV 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 PO/IV Q6H x 4 doses per day 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) SC/IV once per day starting on day 6, given until WBC >5 x 10⁹/L
• Trimethoprim/Sulfamethoxazole (Bactrim DS) prophylaxis recommended

28-day cycles x 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. 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

NK/T-cell lymphoma

Untreated

SMILE

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

Regimen

Phase II

• 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
  • 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.
• 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
• 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)
• 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 ≥3 liters per day on days 1 to 4
• Filgrastim (Neupogen) 300 mcg SC once per day, starting on day 6, given until ANC >1 x 10⁹/L
• 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 (note: was spelled in the protocol as "chlorphenarime") 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

up to 6 cycles given; paper and supplement did not specify the length of each cycle, but other SMILE regimens, e.g. Yamaguchi et al. 2011 above, 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

Relapsed/refractory

SMILE

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

Regimen

Phase II

• 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
  • 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.
• 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
• 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)
• 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
• Patients told to drink at least 2 liters of fluid per day on days 1 to 4; target urine output of ≥3 liters per day on days 1 to 4
• Filgrastim (Neupogen) 300 mcg SC once per day, starting on day 6, given until ANC >1 x 10⁹/L
• 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 (note: was spelled in the protocol as "chlorphenarime") 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

up to 6 cycles given; paper and supplement did not specify the length of each cycle, but other SMILE regimens, e.g. Yamaguchi et al. 2011 above, 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

Peripheral T-cell Lymphoma (PTCL)

Untreated

CHOEP-14 -> upfront autologous SCT

CHOEP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Etoposide, Prednisone

Regimen, d'Amore et al. 2012 (NLG-T-01)

Phase II

Etoposide is omitted for patients older than 60 years of age.

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
• Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
• Prednisone (Sterapred) 50 mg PO BID on days 1 to 5

14-day cycle x 6 cycles

If patients in PR or CR after three cycles, stem cells are mobilized off of cycles 5 and 6, followed by:

• BEAM or BEAC autologous stem cell transplant

References

1. d'Amore F, Relander T, Lauritzsen GF, Jantunen E, Hagberg H, Anderson H, Holte H, Österborg A, Merup M, Brown P, Kuittinen O, Erlanson M, Østenstad B, Fagerli UM, Gadeberg OV, Sundström C, Delabie J, Ralfkiaer E, Vornanen M, Toldbod HE. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012 Sep 1;30(25):3093-9. Epub 2012 Jul 30. link to original article contains verified protocol PubMed

CHOP

CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Synonyms: CHOP-21, ACOP, CAVP, COPA, VACP, VCAP

Structured Concept: C9549 (NCI-T), C0055598 (NCI-MT/UMLS)

Regimen, Simon et al. 2010 (GOELAMS LTP95)

Phase III

The evaluation arm, VIP-rABVD, was not superior and is not included here.

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose per cycle: 2 mg) IV once on day 1
• Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5

21-day cycles x 8 cycles

Radiation therapy for initial bulky disease

"Initial bulky disease": patients with "diameter ≥5 cm"

• Radiation therapy, 40 Gy at 1.8 Gy/day to the involved field

References

1. Simon A, Peoch M, Casassus P, Deconinck E, Colombat P, Desablens B, Tournilhac O, Eghbali H, Foussard C, Jaubert J, Vilque JP, Rossi JF, Lucas V, Delwail V, Thyss A, Maloisel F, Milpied N, le Gouill S, Lamy T, Gressin R. Upfront VIP-reinforced-ABVD (VIP-rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS-LTP95. Br J Haematol. 2010 Oct;151(2):159-66. Epub 2010 Aug 25. link to original article contains verified protocol PubMed

CHOP -> upfront autologous SCT

CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Regimen, Reimer et al. 2004, 2009

Phase II

This study reports using CHOP but doesn't specify the doses; below is a fairly standard CHOP regimen:

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

21-day cycle x 4 to 6 cycles

If CR obtained after 4 cycles or at least a PR after 6 cycles, patients were mobilized with G-CSF 4 to 6 weeks after, and then proceeded to receive either DexaBEAM or ESHAP induction followed by autologous stem cell transplant. Details are not available with regards to the conditioning regimens.

References

1. Reimer P, Schertlin T, Rüdiger T, Geissinger E, Roth S, Kunzmann V, Weissinger F, Nerl C, Schmitz N, Müller-Hermelink HK, Wilhelm M. Myeloablative radiochemotherapy followed by autologous peripheral blood stem cell transplantation as first-line therapy in peripheral T-cell lymphomas: first results of a prospective multicenter study. Hematol J. 2004;5(4):304-11. PubMed
2. Update: Reimer P, Rüdiger T, Geissinger E, Weissinger F, Nerl C, Schmitz N, Engert A, Einsele H, Müller-Hermelink HK, Wilhelm M. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol. 2009 Jan 1;27(1):106-13. Epub 2008 Nov 24. link to original article PubMed
3. Meta-analysis: Abouyabis AN, Shenoy PJ, Sinha R, Flowers CR, Lechowicz MJ. A Systematic Review and Meta-Analysis of Front-line Anthracycline-Based Chemotherapy Regimens for Peripheral T-Cell Lymphoma. ISRN Hematol. 2011;2011:623924. Epub 2011 Jun 16. link to original article PubMed

DD-CHOP

DD-CHOP: Denileukin, Diftitox, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Regimen, Foss et al. 2013 (CONCEPT)

Phase II

• Denileukin diftitox (Ontak) 18 mcg/kg IV over 60 minutes once per day on days 1 & 2
• Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 3
• Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 3
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 3
• Prednisone (Sterapred) 100 mg PO once per day on days 3 to 7

Supportive medications:

• Dexamethasone (Decadron) 4 to 8 mg IV/PO prior to Denileukin diftitox (Ontak)
• Acetaminophen (Tylenol) 650 mg PO prior to Denileukin diftitox (Ontak)
• Diphenhydramine (Benadryl) 25 mg IV prior to Denileukin diftitox (Ontak)
• Normal saline 250 to 500 cc before and after each Denileukin diftitox (Ontak) infusion
• Antiemetics "per institutional standard"
• G-CSF support beginning on day 4

21-day cycles x 6 to 8 cycles

References

1. Foss FM, Sjak-Shie N, Goy A, Jacobsen E, Advani R, Smith MR, Komrokji R, Pendergrass K, Bolejack V. A multicenter phase II trial to determine the safety and efficacy of combination therapy with denileukin diftitox and cyclophosphamide, doxorubicin, vincristine and prednisone in untreated peripheral T-cell lymphoma: the CONCEPT study. Leuk Lymphoma. 2013 Jul;54(7):1373-9. Epub 2013 Jan 29. link to original article contains verified protocol PubMed

Relapsed/refractory

Belinostat (Beleodaq)

Regimen, Pohlman et al. 2009; O'Connor et al. 2013 (BELIEF)

Phase II

• Belinostat (Beleodaq) 1000 mg/m2 IV over 30 minutes once per day on days 1 to 5

3-week cycles

References

1. Abstract: Pohlman, Brad, Advani, Ranjana, Duvic, Madeleine, Hymes, Kenneth B., Intragumtornchai, Tanin, Lekhakula, Arnuparp, Shpilberg, Ofer, Lerner, Adam, Ben-Yehuda, Dina, beylot-Barry, Marie, Hillen, Uwe, Fagerberg, Jan, Foss, Francine M. Final Results of a Phase II Trial of Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma. ASH Annual Meeting Abstracts 2009 114: 920. link to abstract
2. Abstract: Owen A. O'Connor, Tamás Masszi, Kerry J. Savage, Lauren C. Pinter-Brown, Francine M. Foss, Leslie Popplewell, Amanda F. Cashen, Jeanette Doorduijn, Shanta Chawla, Poul Knoblauch, Pier Luigi Zinzani, Peter Brown, Georg Hess, Achiel Van Hoof, Steven M. Horwitz, Andrei R. Shustov. Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL): Results from the BELIEF trial. J Clin Oncol 31, 2013 (suppl; abstr 8507) link to abstract

Bendamustine (Treanda)

Regimen, Demaj et al. 2013 (BENTLY)

Phase II

• Bendamustine (Treanda) 120 mg/m2 IV once per day over 30 to 60 minutes on days 1 & 2

3-week cycles x 6 cycles

References

1. Damaj G, Gressin R, Bouabdallah K, Cartron G, Choufi B, Gyan E, Banos A, Jaccard A, Park S, Tournilhac O, Schiano-de Collela JM, Voillat L, Joly B, Le Gouill S, Saad A, Cony-Makhoul P, Vilque JP, Sanhes L, Schmidt-Tanguy A, Bubenheim M, Houot R, Diouf M, Marolleau JP, Béné MC, Martin A, Lamy T. Results from a prospective, open-label, phase II trial of bendamustine in refractory or relapsed T-cell lymphomas: the BENTLY trial. J Clin Oncol. 2013 Jan 1;31(1):104-10. Epub 2012 Oct 29. link to original article contains verified protocol PubMed

Brentuximab vedotin (Adcetris)

Regimen, Horwitz et al. 2014

Phase II

• Brentuximab vedotin (Adcetris) 1.8 mg/kg IV on day 1

3-week cycle until progression or unacceptable toxicity

References

1. Horwitz SM, Advani RH, Bartlett NL, Jacobsen ED, Sharman JP, O'Connor OA, Siddiqi T, Kennedy DA, Oki Y. Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood. 2014 May 15;123(20):3095-100. Epub 2014 Mar 20. link to original article contains verified protocol PubMed

Lenalidomide (Revlimid)

Regimen, Morschhauser et al. 2013 (EXPECT)

Phase II

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

28-day cycles, up to 2 years

References

1. Morschhauser F, Fitoussi O, Haioun C, Thieblemont C, Quach H, Delarue R, Glaisner S, Gabarre J, Bosly A, Lister J, Li J, Coiffier B. A phase 2, multicentre, single-arm, open-label study to evaluate the safety and efficacy of single-agent lenalidomide (Revlimid®) in subjects with relapsed or refractory peripheral T-cell non-Hodgkin lymphoma: The EXPECT trial. Eur J Cancer. 2013 Sep;49(13):2869-76. Epub 2013 May 31. link to original article contains protocol PubMed

Pralatrexate (Folotyn)

Example orders

• Example orders for Pralatrexate (Folotyn) in peripheral T-cell lymphoma

Regimen, O'Connor et al. 2011 (PROPEL)

Phase II

• Pralatrexate (Folotyn) 30 mg/m2 IV push over 3 to 5 minutes once per day on days 1, 8, 15, 22, 29, 36

Supportive medications:

• Cyanocobalamin (Vitamin B12) 1 mg IM once every 8 to 10 weeks
• Folic acid (Folate) 1 to 1.25 mg PO once per day
  • "Elevated methylmalonic acid (>200 nmol/L) and/or homocysteine (>10 μmol/L) at screening required initiation of Folic acid (Folate) and Cyanocobalamin (Vitamin B12) ≥ 10 days before the first dose of Pralatrexate (Folotyn)."

7-week cycles, given until progression of disease, unacceptable toxicity, or patient/physician preference

References

1. O'Connor OA, Pro B, Pinter-Brown L, Bartlett N, Popplewell L, Coiffier B, Lechowicz MJ, Savage KJ, Shustov AR, Gisselbrecht C, Jacobsen E, Zinzani PL, Furman R, Goy A, Haioun C, Crump M, Zain JM, Hsi E, Boyd A, Horwitz S. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011 Mar 20;29(9):1182-9. link to original article contains verified protocol PubMed

Romidepsin (Istodax)

Regimen, Coiffier et al. 2012

Phase II

• Romidepsin (Istodax) 14 mg/m2 IV over 4 hours once per day on days 1, 8, 15

28-day cycles, up to 6 cycles, with optional extension of treatment for patients with stable disease or response

References

1. Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, Caballero D, Borchmann P, Morschhauser F, Wilhelm M, Pinter-Brown L, Padmanabhan S, Shustov A, Nichols J, Carroll S, Balser J, Balser B, Horwitz S. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012 Feb 20;30(6):631-6. Epub 2012 Jan 23. link to original article contains verified protocol PubMed