Cutaneous T-cell lymphoma

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Bhagirathbhai Dholaria, MBBS
Vanderbilt University
Nashville, TN
14 regimens on this page
16 variants on this page

Contents


Guidelines

ESMO

NCCN

Upfront therapy

PUVA

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PUVA: Psoralen & Ultra-Violet A

Regimen

Study Evidence Comparator Comparative Efficacy
Edelson et al. 1987 Non-randomized (RT)
Whittaker et al. 2012 (EORTC 21011) Phase III (C) PUVA & Bexarotene Seems not superior

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

References

  1. Edelson R, Berger C, Gasparro F, Jegasothy B, Heald P, Wintroub B, Vonderheid E, Knobler R, Wolff K, Plewig G, McKiernan G, Christiansen I, Oster M, Honigsmann H, Wilford H, Kokoschka E, Rehle T, Perez M, Stingl G, Laroche L. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy: preliminary results. N Engl J Med. 1987 Feb 5;316(6):297-303. link to original article PubMed
  2. EORTC 21011: Whittaker S, Ortiz P, Dummer R, Ranki A, Hasan B, Meulemans B, Gellrich S, Knobler R, Stadler R, Karrasch M. Efficacy and safety of bexarotene combined with psoralen-ultraviolet A (PUVA) compared with PUVA treatment alone in stage IB-IIA mycosis fungoides: final results from the EORTC Cutaneous Lymphoma Task Force phase III randomized clinical trial (NCT00056056). Br J Dermatol. 2012 Sep;167(3):678-87. link to original article PubMed

Topical therapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Kaye et al. 1989 Randomized, >20 pts CAV-E & RT Seems not superior

Usually consists of high-dose topical steroids or nitrogen mustards; see paper for details.

References

  1. Kaye FJ, Bunn PA Jr, Steinberg SM, Stocker JL, Ihde DC, Fischmann AB, Glatstein EJ, Schechter GP, Phelps RM, Foss FM, Parlette HL, Anderson MJ, Sausville EA. A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med. 1989 Dec 28;321(26):1784-90. link to original article PubMed

Relapsed or refractory

Alemtuzumab monotherapy

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Regimen

Study Evidence Efficacy
Lundin et al. 2003 Phase II ORR: 55%

Chemotherapy

  • Alemtuzumab (Campath) as follows:
    • 3 mg IV once on day 1, then
    • Increased to 10 mg IV once as soon as infusion-related reactions tolerated, then
    • Increased to 30 mg IV once as soon as infusion-related reactions tolerated, then
    • 30 mg IV 3 days per week

Up to 12-week course

References

  1. Lundin J, Hagberg H, Repp R, Cavallin-Ståhl E, Fredén S, Juliusson G, Rosenblad E, Tjønnfjord G, Wiklund T, Osterborg A. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome. Blood. 2003 Jun 1;101(11):4267-72. Epub 2003 Jan 23. link to original article contains protocol PubMed

Belinostat monotherapy

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Regimen

Study Evidence Efficacy
Foss et al. 2014 Phase II ORR: 14%

Chemotherapy

21-day cycles

References

  1. Foss F, Advani R, Duvic M, Hymes KB, Intragumtornchai T, Lekhakula A, Shpilberg O, Lerner A, Belt RJ, Jacobsen ED, Laurent G, Ben-Yehuda D, Beylot-Barry M, Hillen U, Knoblauch P, Bhat G, Chawla S, Allen LF, Pohlman B. A phase II trial of belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. Br J Haematol. 2015 Mar;168(6):811-9. Epub 2014 Nov 17. link to original article contains protocol PubMed

Bendamustine monotherapy

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Regimen

Study Evidence Efficacy
Demaj et al. 2013 (BENTLY) Phase II ORR: 50%

Chemotherapy

21-day cycle for 6 cycles

References

  1. BENTLY: 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 monotherapy

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Variant #1, 48 weeks

Study Evidence Comparator Comparative Efficacy
Prince et al. 2017 (ALCANZA) Phase III (C) Brentuximab vedotin Inferior OGRR at 4 months

This dose is considered the target dose in ALCANZA.

Chemotherapy

48-week course

Variant #2, indefinite

Study Evidence Comparator Comparative Efficacy
Duvic et al. 2001a Phase II (RT) ORR: 55%
Duvic et al. 2001b Phase II/III (E-RT) Bexarotene; 6.5 mg/m2/d Superior ORR

Note: This dose is considered the optimal starting dose by Duvic et al. 2001a.

Chemotherapy

Continued indefinitely

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
  3. ALCANZA: Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P, Zinzani PL, Wolter P, Sanches JA, Ortiz-Romero PL, Akilov OE, Geskin L, Trotman J, Taylor K, Dalle S, Weichenthal M, Walewski J, Fisher D, Dréno B, Stadler R, Feldman T, Kuzel TM, Wang Y, Palanca-Wessels MC, Zagadailov E, Trepicchio WL, Zhang W, Lin HM, Liu Y, Huebner D, Little M, Whittaker S, Duvic M; ALCANZA study group. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017 Aug 5;390(10094):555-566. Epub 2017 Jun 7. link to original article contains verified protocol PubMed

Bexarotene & Pralatrexate

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Regimen

Study Evidence Efficacy
Duvic et al. 2017 Phase I/II ORR: 60%

This dose is the MTD. Note that the abstract contains a typo for bexarotene dosing; the authors have been contacted.

Chemotherapy

28-day cycles

References

  1. Duvic M, Kim YH, Zinzani PL, Horwitz SM. Results from a phase I/II open-label, dose-finding study of pralatrexate and oral bexarotene in patients with relapsed/refractory cutaneous T-cell lymphoma. Clin Cancer Res. 2017 Jul;23(14):3552-6. Epub 2017 Feb 6. link to original article contains verified protocol link to PMC article PubMed

Brentuximab vedotin monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Kim et al. 2015 (SU-06212011-7946) Phase II OGRR: 70% (90% CI, 53-83)
Duvic et al. 2015 Phase II ORR: 73% (95% CI, 60-86)
Prince et al. 2017 (ALCANZA) Phase III (E-RT) Investigator's choice of:
1. Bexarotene
2. Methotrexate
Superior OGRR at 4 months

Chemotherapy

21-day cycle for up to 16 cycles

References

  1. SU-06212011-7946: Kim YH, Tavallaee M, Sundram U, Salva KA, Wood GS, Li S, Rozati S, Nagpal S, Krathen M, Reddy S, Hoppe RT, Nguyen-Lin A, Weng WK, Armstrong R, Pulitzer M, Advani RH, Horwitz SM. Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sézary syndrome with variable CD30 expression level: A multi-institution collaborative project. J Clin Oncol. 2015 Nov 10;33(32):3750-8. Epub 2015 Jul 20. link to original article contains verified protocol link to PMC article PubMed
  2. Duvic M, Tetzlaff MT, Gangar P, Clos AL, Sui D, Talpur R. Results of a phase II trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma and lymphomatoid papulosis. J Clin Oncol. 2015 Nov 10;33(32):3759-65. Epub 2015 Aug 10. link to original article contains verified protocol link to PMC article PubMed
  3. ALCANZA: Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P, Zinzani PL, Wolter P, Sanches JA, Ortiz-Romero PL, Akilov OE, Geskin L, Trotman J, Taylor K, Dalle S, Weichenthal M, Walewski J, Fisher D, Dréno B, Stadler R, Feldman T, Kuzel TM, Wang Y, Palanca-Wessels MC, Zagadailov E, Trepicchio WL, Zhang W, Lin HM, Liu Y, Huebner D, Little M, Whittaker S, Duvic M; ALCANZA study group. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017 Aug 5;390(10094):555-566. Epub 2017 Jun 7. link to original article contains verified protocol PubMed

Denileukin diftitox monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Olsen et al. 2001 (L4389-10) Phase III (E-RT) Denileukin diftitox; 9 mcg/kg Seems not superior
Prince et al. 2010 (L4389-11) Phase III (E-RT) 1. Denileukin diftitox; 9 mcg/kg Superior ORR
2. Placebo Superior PFS

Note: Dose is that which was recommended in L4389-11 based on superior response. Up to 3 additional cycles allowed in L4389-10 for patients who had ongoing response.

Chemotherapy

Supportive medications

21-day cycles for up to 8 cycles (see note)

References

  1. L4389-10: 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. L4389-11: 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. 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 monotherapy

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Regimen

Study Evidence Efficacy
Querfeld et al. 2013 Phase II ORR: 28%

Chemotherapy

  • Lenalidomide (Revlimid) as follows:
    • Cycle 1: 10 mg PO once per day on days 1 to 21
    • Cycle 2, if tolerated: 15 mg PO once per day on days 1 to 21
    • Cycle 3, if tolerated: 20 mg PO once per day on days 1 to 21
    • Cycle 4 onwards, if tolerated: 25 mg PO once per day on days 1 to 21

28-day cycle for up to 26 cycles (2 years)

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

Methotrexate monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Prince et al. 2017 (ALCANZA) Phase III (C) Brentuximab vedotin Inferior OGRR at 4 months

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

28-day cycle for 12 cycles

References

  1. Retrospective: Zackheim HS, Kashani-Sabet M, McMillan A. Low-dose methotrexate to treat mycosis fungoides: a retrospective study in 69 patients. J Am Acad Dermatol. 2003 Nov;49(5):873-8. link to original article PubMed
  2. ALCANZA: Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P, Zinzani PL, Wolter P, Sanches JA, Ortiz-Romero PL, Akilov OE, Geskin L, Trotman J, Taylor K, Dalle S, Weichenthal M, Walewski J, Fisher D, Dréno B, Stadler R, Feldman T, Kuzel TM, Wang Y, Palanca-Wessels MC, Zagadailov E, Trepicchio WL, Zhang W, Lin HM, Liu Y, Huebner D, Little M, Whittaker S, Duvic M; ALCANZA study group. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017 Aug 5;390(10094):555-566. Epub 2017 Jun 7. link to original article contains verified protocol PubMed

Mogamulizumab monotherapy

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Variant #1, 8-week course

Study Evidence
Ogura et al. 2014 (KW-0761-004) Phase II

Chemotherapy

28-day cycle for 2 cycles

Variant #2, indefinite

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Duvic et al. 2015 (KW-0761-001) Phase I/II
Kim et al. 2018 (MAVORIC) Phase III (E-RT) Vorinostat Superior PFS

Note: in KW-0761-001, a two-week "period of observation" was undertaken after cycle 1.

Chemotherapy

  • Mogamulizumab (Poteligeo) as follows:
    • Cycle 1: 1 mg/kg IV once per day on days 1, 8, 15, 22
    • Subsequent cycles: 1 mg/kg IV once per day on days 1 & 15

28-day cycles

References

  1. KW-0761-004: Ogura M, Ishida T, Hatake K, Taniwaki M, Ando K, Tobinai K, Fujimoto K, Yamamoto K, Miyamoto T, Uike N, Tanimoto M, Tsukasaki K, Ishizawa K, Suzumiya J, Inagaki H, Tamura K, Akinaga S, Tomonaga M, Ueda R. Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol. 2014 Apr 10;32(11):1157-63. Epub 2014 Mar 10. link to original article contains protocol PubMed
  2. KW-0761-001: Duvic M, Pinter-Brown LC, Foss FM, Sokol L, Jorgensen JL, Challagundla P, Dwyer KM, Zhang X, Kurman MR, Ballerini R, Liu L, Kim YH. Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. Blood. 2015 Mar 19;125(12):1883-9. Epub 2015 Jan 20. link to original article contains protocol PubMed
  3. MAVORIC: Kim YH, Bagot M, Pinter-Brown L, Rook AH, Porcu P, Horwitz SM, Whittaker S, Tokura Y, Vermeer M, Zinzani PL, Sokol L, Morris S, Kim EJ, Ortiz-Romero PL, Eradat H, Scarisbrick J, Tsianakas A, Elmets C, Dalle S, Fisher DC, Halwani A, Poligone B, Greer J, Fierro MT, Khot A, Moskowitz AJ, Musiek A, Shustov A, Pro B, Geskin LJ, Dwyer K, Moriya J, Leoni M, Humphrey JS, Hudgens S, Grebennik DO, Tobinai K, Duvic M; MAVORIC Investigators. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2018 Sep;19(9):1192-1204. Epub 2018 Aug 9. link to original article contains protocol PubMed

Placebo

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Regimen

Study Evidence Comparator Comparative Efficacy
Prince et al. 2010 (L4389-11) Phase III (C) Denileukin diftitox Inferior PFS

References

  1. L4389-11: 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

Pralatrexate monotherapy

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Regimen

Study Evidence Efficacy
Horwitz et al. 2012 Phase II RR: 45%

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

Chemotherapy

Supportive medications

28-day cycles

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 monotherapy

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Regimen

Study Evidence Efficacy
Piekarz et al. 2009 Phase II (RT) ORR: 34% (95% CI, 23-46)
Whittaker et al. 2010 (GPI-04-0001) Phase II (RT) ORR: 34% (95% CI, 25-45)

Chemotherapy

28-day cycle for up to 6 cycles; optional extension of treatment for patients with SD or better

References

  1. Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH, Zain J, Prince HM, Leonard JP, Geskin LJ, Reeder C, Joske D, Figg WD, Gardner ER, Steinberg SM, Jaffe ES, Stetler-Stevenson M, Lade S, Fojo AT, Bates SE. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009 Nov 10;27(32):5410-7. Epub 2009 Oct 13. link to original article contains verified protocol link to PMC article PubMed
  2. GPI-04-0001: 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 monotherapy

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Regimen

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Duvic et al. 2006 Phase IIa (RT) ORR: 24%
Olsen et al. 2007 Phase IIb (RT) ORR: 30%
Kim et al. 2018 (MAVORIC) Phase III (C) Mogamulizumab Inferior PFS

Note: Duvic et al. 2006 evaluated several different doses, but this is the one that "had the most favorable safety profile". To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

Continued indefinitely

References

  1. Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, Chiao JH, Reilly JF, Ricker JL, Richon VM, Frankel SR. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood. 2007 Jan 1;109(1):31-9. Epub 2006 Sep 7. Erratum in: Blood. 2007 Jun 15;109(12):5086. link to original article link to PMC article contains protocol PubMed
  2. 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
    1. Update: Duvic M, Olsen EA, Breneman D, Pacheco TR, Parker S, Vonderheid EC, Abuav R, Ricker JL, Rizvi S, Chen C, Boileau K, Gunchenko A, Sanz-Rodriguez C, Geskin LJ. Evaluation of the long-term tolerability and clinical benefit of vorinostat in patients with advanced cutaneous T-cell lymphoma. Clin Lymphoma Myeloma. 2009 Dec;9(6):412-6. link to SD article PubMed
  3. MAVORIC: Kim YH, Bagot M, Pinter-Brown L, Rook AH, Porcu P, Horwitz SM, Whittaker S, Tokura Y, Vermeer M, Zinzani PL, Sokol L, Morris S, Kim EJ, Ortiz-Romero PL, Eradat H, Scarisbrick J, Tsianakas A, Elmets C, Dalle S, Fisher DC, Halwani A, Poligone B, Greer J, Fierro MT, Khot A, Moskowitz AJ, Musiek A, Shustov A, Pro B, Geskin LJ, Dwyer K, Moriya J, Leoni M, Humphrey JS, Hudgens S, Grebennik DO, Tobinai K, Duvic M; MAVORIC Investigators. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2018 Sep;19(9):1192-1204. Epub 2018 Aug 9. link to original article contains protocol PubMed

Relapsed or refractory, subsequent lines of treatment

Denileukin diftitox monotherapy

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Regimen

Study Evidence
Duvic et al. 2012 Non-randomized

Chemotherapy

21-day cycle for up to 8 cycles

References

  1. 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 contains protocol PubMed