NCCN Guidelines Version Mycosis Fungoides/Sezary Syndrome

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1 DIAGNOSIS ESSENTIAL: Biopsy of suspicious skin sites Dermatopathology review of slides USEFUL UNDER CERTAIN CIRCUMSTANCES: Immunohistochemical studies of skin biopsy a,b (CD2, CD3, CD4, CD5, CD7, CD8, CD2, CD3, CD26, CD56, TIA1, granzyme B, βf1) Molecular study f T-cell recept (TCR) gene rearrangements (assessment of clonality) of skin biopsy; a PCR methodsc Assessment of peripheral blood f Sezary cells (in cases where skin is not diagnostic, especially T4) including Sezary cell prep, flow cytometry and PCR f TCR gene rearrangement Biopsy of suspicious lymph nodes (in absence of definitive skin diagnosis) Assessment of ATLL serology PCR in at-risk populations NCCN Guidelines Version WORKUP ESSENTIAL: Complete physical examination TCR gene rearrangement of Examination of entire skin: peripheral blood lymphocytes if assessment of %BSA (palm plus digits Sezary Syndrome suspected 1%BSA) and type of skin lesion Comprehensive metabolic panel (patch/plaque, tum, erythroderma) LDH Palpation of peripheral lymph node Imaging studies regions Neck/chest/abdominal/pelvic Palpation f ganomegaly/masses contrast-enhanced CT Labaty studies: d integrated whole body PET-CT CBC with Sezary screen (manual slide ( T2, large cell transfmed review, "Sezary cell prep") folliculotropic MF, with Sezary flow cytometric study (optional palpable adenopathy f T1); CD3, CD4, CD7, CD8, CD26 to abnmal labaty studies) assess f expanded CD4+ cells with Pregnancy testing in women of increased CD4/CD8 ratio with child-bearing agee abnmal immunophenotype including loss of CD7 CD26 USEFUL IN SELECTED CASES: Bone marrow biopsy (not required f staging but used to document visceral disease in those suspected to have marrow involvement including B2 blood involvement and in patients with unexplained hematologic abnmality) Biopsy of suspicious lymph nodes identical clones (recommend assessment of clonality f all but particularly NCI LN 2-3) suspected extracutaneous sites Rebiopsy if suspicious of large cell transfmation aclinically histologically non-diagnostic cases. Pimpinelli N, Olsen EA, Santucci M, et all cases of. Demonstration of al., f the International Society f Cutaneous Lymphoma. Defining early mycosis identical clones in skin, blood and/ lymph node may be helpful in selected fungoides. J Am Acad Dermatol 25;53: cases. bsee Use of Immunophenotyping and Genetic Testing in Differential Diagnosis of Mature d Sezary syndrome (B2) is as defined on MFSS-2. B-cell and T/NK-cell Neoplasms (NHODG-A). emany skin-directed and systemic therapies are contraindicated of ctcr gene rearrangement results should be interpreted with caution. TCR clonal unknown safety in pregnancy. Refer to individual drug infmation. rearrangement can be seen in non-malignant conditions may not be demonstrated in Note: All recommendations are categy 2A unless otherwise indicated. STAGE ( MFSS-2) Stage IA Stage IB-IIA Stage IIB Stage III Stage IV See Primary Treatment (MFSS-4) See Primary Treatment (MFSS-5) See Primary Treatment (MFSS-6) See Primary Treatment (MFSS-7) See Primary Treatment (MFSS-8) Version 4.211, 8/24/11 National Comprehensive Cancer Netwk, Inc. 211, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MFSS-1

2 NCCN Guidelines Version TNMB f Skin Node Visceral T1 T2 T3 T4 N N1 N2 N3 NX M M1 TNMB Classification and Staging of Mycosis Fungoides and Sezary Syndrome g Limited patches, hpapules and/ plaquesicovering < 1 % of the skin surface h i Patches, papules and/ plaques covering 1 % of the skin surface One me tums j ( 1 cm in diameter) Confluence of erythema 8 % body surface area No clinically abnmal peripheral lymph nodes; biopsy not required k Clinically abnmal peripheral lymph nodes; histopathology Dutch Gr 1 NCI LN -2 Clinically abnmal peripheral lymph nodes; histopathology Dutch Gr 2 NCI LN 3 Clinically abnmal peripheral lymph nodes; histopathology Dutch Gr 3-4 NCI LN 4 Clinically abnmal peripheral lymph nodes; no histologic confirmation No visceral gan involvement Visceral involvement (must have pathology confirmationl and gan involved should be specified) Blood B Absence of significant blood involvement: 5 % of peripheral blood lymphocytes are atypical (Sezary) cellsm B1 Low blood tum burden: > 5 % of peripheral blood lymphocytes are atypical (Sezary) cells but does not meet the criteria of B2 B2 High blood tum burden: 1/mcL Sezary cellsl Olsen E, Vonderheid E, Pimpinelli N, et al. Blood 27;11: of large cell transfmation has occurred. Phenotyping f CD3 is encouraged. Sezary syndrome (B2) is defined as a clonal rearrangement of the TCR in the kabnmal peripheral lymph node(s) = any palpable peripheral node that on physical blood (clones should be relevant to clone in the skin) and either 1/mcL increased CD4 CD3 cells with CD4/CD8 of 1 me increase in CD4 cells examination is firm, irregular, clustered, fixed 1.5 cm in diameter. Node groups with an abnmal phenotype (4% CD4/CD7 3% CD4/CD26). f g hpatch = Any size skin lesion without significant elevation induration. Presence/absence of hypo- hyperpigmentation, scale, crusting and/ poikiloderma should be noted. iplaque = Any size skin lesion that is elevated indurated. Presence absence of scale, crusting and/ poikiloderma should be noted. Histological features such as folliculotropism large cell transfmation ( 25 % large cells), CD3+ CD3- and clinical features such as ulceration are imptant to document. j Tum = at least one > 1 cm diameter solid nodular lesion with evidence of depth and/ vertical growth. Note total number of lesions, total volume of lesions, largest size lesion, and region of body involved. Also note if histological evidence examined on physical examination = cervical, supraclavicular, epitrochlear, axillary and inguinal. Central nodes, which are not generally amenable to pathologic assessment, are not currently considered in the nodal classification unless used to establish N3 histopathologically. lspleen and liver may be diagnosed by imaging criteria. msezary cells are defined as lymphocytes with hyperconvoluted cerebrifm nuclei. If Sezary cells are not able to be used to determine tum burden f B2, then one of the following modified ISCL criteria along with a positive clonal rearrangement of the TCR may be used instead. (1) expanded CD4+ CD3+ cells with CD4/CD8 ratio 1, (2) expanded CD4+ cells with abnmal immunophenotype including loss of CD7 CD26. Note: All recommendations are categy 2A unless otherwise indicated. Version 4.211, 8/24/11 National Comprehensive Cancer Netwk, Inc. 211, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MFSS-2

3 NCCN Guidelines Version Clinical Staging/Classification of MF and SS f T N M B IA IB 1 2,1,1 II IIB ,2-2,1,1 III IIIA IIIB ,1 1 IVA IVA IVB f Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the Staging and Classification of Mycosis Fungoides and Sezary Syndrome: A Proposal of the International Society f Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Fce of the European Organization of Research and Treatment of Cancer (EORTC). Blood 27;11: Note: All recommendations are categy 2A unless otherwise indicated. Version 4.211, 8/24/11 National Comprehensive Cancer Netwk, Inc. 211, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MFSS-3

4 NCCN Guidelines Version STAGE ( MFSS-2) PRIMARY TREATMENT o Stage IA Skin-directed therapies (may be alone in combination with other skin-directed therapies): See Suggested Treatment Regimens "Skin-directed therapies (skin-limited/local)" (MFSS-A) If B1 blood involvement, consider primary treatment f Stage III, B1 MFSS-7 (categy 2B) CR/PRp Refracty to > stage IA on skindirected therapies Relapse with persistent T1 skin disease Systemic therapy ± skindirected therapy ( see Stage IB on page MFSS-5) Total skin electron beam therapy ( TSEBT) Clinical trial Histologic evidence of folliculotropic large cell transfmed MF n See Primary Treatment f Stage IIB on page MFSS-6 n Folliculotropic, large cell transfmed MF, B1 involvement has been associated with wse outcome, thus, may be managed as "tum (IIB)" disease ( MFSS-6) stage III with B1 involvement ( MFSS-7), respectively. oit is preferred that treatment occur at centers with expertise in the management of the disease. ppatients achieving a should be considered f maintenance taper regimens to optimize duration. Patients who relapse often respond well to the same treatment. Patients with a PR should be treated with the other options in the primary treatment list to improve befe moving onto treatment f refracty disease. Patients with relapse persistent disease after initial primary treatment may be candidates f clinical trials. qrefracty intolerant to multiple previous therapies. Note: All recommendations are categy 2A unless otherwise indicated. Version 4.211, 8/24/11 National Comprehensive Cancer Netwk, Inc. 211, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MFSS-4

5 NCCN Guidelines Version STAGE ( MFSS-2) PRIMARY TREATMENT o Stage IB-IIA Generalized skin treatment See Suggested Treatment Regimens "Skin-directed therapies (Skingeneralized) (MFSS-A) ± adjuvant local skin treatmentr ( see stage IA on MFSS-4) If blood B1 involvement, consider primary treatment f Stage IIIB B1 MFSS-7 (categy 2B) CR/PRp Refracty to > stage IB-IIA Relapse with persistent T1- T2 disease: T1 ( see stage IA on MFSS-4) T2 (see generalized skin treatment) ( MFSS-A) See Suggested Treatment Regimens Clinical trial Systemic Therapies (SYST-CAT A) (MFSS-A) Combination Therapies ± skin-directed therapy CR/PRp Refracty Clinical trial TSEBT (if not previously administered) Systemic chemotherapy agents used in stage IIB disease See Suggested Treatment Regimens "Systemic Therapies (SYST-CAT B) " (MFSS-A) Histologic evidence of folliculotropic large cell transfmed MF n See Primary Treatment f Stage IIB on page MFSS-6 nfolliculotropic, large cell transfmed MF, B1 involvement has been associated with wse outcome, thus, may be managed as "tum (IIB)" disease ( MFSS-6) stage III with B1 involvement ( MFSS-7), respectively. oit is preferred that treatment occur at centers with expertise in the management of the disease. ppatients achieving a should be considered f maintenance taper regimens to optimize duration. Patients who relapse often respond well to the same treatment. Patients with a PR should be treated with the other options in the primary treatment list to improve befe moving onto treatment f refracty disease. Patients with relapse persistent disease after initial primary treatment may be candidates f clinical trials. qrefracty intolerant to multiple previous therapies. rf patients with recalcitrant sites after generalized skin treatment, additional local treatment may be needed. Note: All recommendations are categy 2A unless otherwise indicated. Version 4.211, 8/24/11 National Comprehensive Cancer Netwk, Inc. 211, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MFSS-5

6 NCCN Guidelines Version STAGE ( MFSS-2) Stage IIB s and/ histologic evidence of folliculotropic large cell transfmation (LCT) Limited extent tum disease ± patch/plaque disease Generalized extent tum, transfmed, and/ folliculotropic disease t PRIMARY TREATMENT o Local RT f limited extent tum, transfmed, and/ folliculotrophic diseaseu Systemic Therapies (SYST- CAT A) (MFSS-A) ± skindirected therapies v ± RT TSEBT w See Suggested Treatment Regimenst Systemic Therapies (SYST-CAT A) (MFSS-A) Systemic Therapies (SYST-CAT B) (MFSS-A) Systemic Therapies (SYST-CAT C) (MFSS-A) t Combination Therapies ± skin-directed therapy oit is preferred that treatment occur at centers with expertise in the management of the disease. u ppatients achieving a should be considered f maintenance taper regimens to optimize duration. Patients who relapse often respond well to the same treatment. Patients with a PR should be treated with the other v options in the primary treatment list to improve befe moving onto w treatment f refracty disease. Patients with relapse persistent disease after initial primary treatment may be candidates f clinical trials. x qrefracty intolerant to multiple previous therapies. srebiopsy if suspect large cell transfmation. y CR/PR p Refracty CR/PR p Refracty Note: All recommendations are categy 2A unless otherwise indicated. Relapse with persistent T1- T3 limited: T1-2 ( see stage IA on MFSS-4 stage IB-IIA on MFSS-5) T3 limited extent Relapse with persistent T1-T3: T1-2 ( see stage IA on MFSS-4 stage IB-IIA on MFSS-5) T3 Multi-agent chemotherapyx Consider allogeneic transplanty Clinical trial t Histologic evidence of LCT often, but not always cresponds to a me aggressive growth rate. If there is no evidence of me aggressive growth, choosing systemic therapies from SYST-CAT A SYST-CAT B are appropriate. If aggressive growth is seen, then agents listed in SYST-CAT C are preferred. F non-radiated sites, see Stage I-IIA. After patient is rendered disease free by RT, may consider adjuvant systemic biologic therapy ( SYST-CAT A) after RT to improve duration. Skin-directed therapies are f patch plaque lesions and not f tum lesions. May consider adjuvant systemic biologic therapy ( SYST-CAT A) after TSEBT to improve duration. Most patients are treated with multiple SYST-CAT A/B Combination therapies befe receiving multiagent chemotherapy. The role of allogeneic HSCT is controversial. See discussion f further details. Version 4.211, 8/24/11 National Comprehensive Cancer Netwk, Inc. 211, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MFSS-6

7 NCCN Guidelines Version STAGE ( MFSS-2) PRIMARY TREATMENT o Stage III z If no blood involvement, consider skin-directed therapy See Suggested Treatment Regimens Skin-directed therapies (Skin-generalized) (MFSS-A) If blood B1 involvement, systemic therapies See Suggested Treatment Regimens "Systemic Therapies (SYST-CAT A)" ± skindirected therapy aa CR/PR p Refracty Relapse persistent disease oit is preferred that treatment occur at centers with expertise in the management of the disease. ppatients achieving a should be considered f maintenance taper regimens to optimize duration. Patients who relapse often respond well to the same treatment. Patients with a PR should be treated with the other options in the primary treatment list to improve befe moving onto treatment f refracty disease. Patients with relapse persistent disease after initial primary treatment may be candidates f clinical trials. qrefracty intolerant to multiple previous therapies. ythe role of allogeneic HSCT is controversial. See discussion f further details. zgeneralized skin-directed therapies (other than topical steroids) may not be well-tolerated in stage III and should be used with caution. Phototherapy (PUVA UVB) TSEBT can be used successfully. Combination therapies See Suggested Treatment Regimens - Combination Therapies bb (MFSS-A) Clinical trial CR/PRp Refracty aamid-potency topical steroids should be included (± occlusive modality) with any of the primary treatment modalities to reduce skin symptoms. Erythrodermic patients are at increased risk f secondary infection with skin pathogens and systemic antibiotic therapy should be considered. bbcombination therapy options can be considered earlier (primary treatment) depending on treatment availability symptom severity. ccalemtuzumab can be administered by IV subcutaneously. Lower doses administered subcutaneously have shown lower incidence of infectious complications. Note: All recommendations are categy 2A unless otherwise indicated. Relapse persistent disease Clinical trial See Suggested Treatment Regimens "Systemic Therapies (SYST-CAT B)" Alemtuzumabcc Consider non-ablative allogeneic transplant, y as appropriate Version 4.211, 8/24/11 National Comprehensive Cancer Netwk, Inc. 211, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MFSS-7

8 NCCN Guidelines Version STAGE ( MFSS-2) PRIMARY TREATMENT o Stage IV Sezary syndrome See Suggested Treatment Regimens Systemic Therapies (SYST-CAT A) (MFSS-A) Combination Therapies CR/PR p Refracty Relapse persistent disease Consider allogeneic transplant, y as appropriate See Suggested Treatment Regimens - Systemic Therapies (SYST-CAT B) (MFSS-A) Alemtuzumabcc Clinical trial Non Sezary Visceral disease (solid gan) See Suggested Treatment Regimens - Systemic Therapies (SYST-CAT B) ( SYST-CAT C) dd multiagent chemotherapy ± RT f local controlee CR/PR p Refracty Relapse persistent disease Consider allogeneic transplant, y as appropriate Clinical trial oit is preferred that treatment occur at centers with expertise in the management of the disease. ppatients achieving a should be considered f maintenance taper regimens to optimize duration. Patients who relapse often respond well to the same treatment. Patients with a PR should be treated with the other options in the primary treatment list to improve befe moving onto treatment f refracty disease. Patients with relapse persistent disease after initial primary treatment may be candidates f clinical trials. qrefracty intolerant to multiple previous therapies. ythe role of allogeneic HSCT is controversial. See discussion f further details. ccalemtuzumab can be administered by IV subcutaneously. Lower doses administered subcutaneously has shown lower incidence of infectious complications. ddpatients with stage IV non-sezary/visceral disease may present with me aggressive growth characteristics. If there is no evidence of me aggressive growth, systemic therapies from SYST-CAT B are appropriate. If aggressive growth is seen, then agents listed in SYST-CAT C are preferred. ee Consider adjuvant systemic biologic therapy ( SYST-CAT A) after chemotherapy to improve duration. Note: All recommendations are categy 2A unless otherwise indicated. Version 4.211, 8/24/11 National Comprehensive Cancer Netwk, Inc. 211, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MFSS-8

9 c SKIN-DIRECTED THERAPIES NCCN Guidelines Version SUGGESTED TREATMENT REGIMENS a SYSTEMIC THERAPIES F limited/localized skin involvement (Skin- Categy A (SYST-CAT A) Limited/Local) Retinoids (bexarotene, all-trans retinoic Topical cticosteroidsb acid, isotretinoin [13-cis-retinoic acid], Topical chemotherapy ( mechlethamine acitretin) [nitrogen mustard], carmustine) Interferons (IFN-alpha, IFN-gamma) Local radiation (particularly unilesional HDAC-inhibits (vinostat, romidepsin) e presentation, Gy) Extracpeal photopheresisf Topical retinoids (bexarotene, tazarotene) Denileukin diftitox Phototherapy (UVB, nbuvb f patch/thin Methotrexate ( 1 mg q week) plaques; PUVA f thicker plaques) c Topical imiquimod Categy B (SYST-CAT B) First-line therapies F generalized skin involvement (Skin- Liposomal doxubicin Generalized) Gemcitabine Topical cticosteroidsb Second-line therapies Topical chemotherapy (mechlethamine Chlambucil [ nitrogen mustard], carmustine) Pentostatin Phototherapy (UVB, nbuvb, f patch/thin Etoposide plaques; PUVA f thicker plaques) c Cyclophosphamide Total skin electron beam therapy (3-36 Gy) d Temozolomide Methotrexate (>1 mg q week) (reserved f those with severe skin symptoms Btezomib generalized thick plaque tum disease, Low dose pralatrexate po to other therapies) a e See references f regimens MFSS-A 2 of 4, MFSS-A 3 of 4, and MFSS-A 4 of 4 blong-term use of topical steroid may be associated with skin atrophy and/ striae fmation. This risk wsens with increased potency of the steroid. High-potency f steroid used on large skin surfaces may lead to systemic absption. d Cumulative dose of UV is associated with increased risk of UV-associated skin neoplasms; thus, phototherapy may not be appropriate in patients with histy of extensive squamoproliferative skin neoplasms basal cell carcinomas who have had melanoma. It is common practice to follow TSEBT with systemic therapies such as interferon bexarotene to maintain. Note: All recommendations are categy 2A unless otherwise indicated. COMBINATION THERAPIES Version 4.211, 8/24/11 National Comprehensive Cancer Netwk, Inc. 211, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SYSTEMIC THERAPIES (continued) Categy C (SYST-CAT C) g Liposomal doxubicin Gemcitabine Denileukin diftitox Romidepsin Low standard dose pralatrexate See regimens listed on TCEL-Bh Skin-directed + Systemic Phototherapy + retinoide Phototherapy + IFN Phototherapy + photopheresisf Total skin electron beam + photopheresisf Systemic + Systemic Retinoid + IFN Bexarotene + denileukin diftitox Photopheresis f + retinoid Photopheresis f + IFN Photopheresis f + retinoid + IFN Safety of combining TSEBT with systemic retinoids HDAC-inhibits, such as vinostat romidepsin combining phototherapy with vinostat romidepsin is unknown. Photopheresis may be me appropriate as systemic therapy in patients with some g h blood involvement (B1 B2). Patients with large cell transfmed (LCT) MF and stage IV non-sezary/visceral disease may present with me aggressive growth characteristics. In general, agents listed in SYST-CAT C are preferred in these circumstances. Combination regimens are generally reserved f patients with relapsed/refraty extracutaneous disease. MFSS-A 1 of 4

10 NCCN Guidelines Version SUGGESTED TREATMENT REGIMENS References Skin-directed therapies Topical cticosteroids Zackheim HS, Kashani Sabet M, Amin S. Topical cticosteroids f mycosis fungoides. Experience in 79 patients. Arch Dermatol 1998;134(8): Zackheim HS. Treatment of patch stage mycosis fungoides with topical cticosteroids. Dermatol Ther 23;16: Carmustine Zackheim HS. Topical carmustine (carmustine) in the treatment of mycosis fungoides. Dermatol Ther 23;16: Nitrogen mustard (mechlethamine hydrochlide) Kim YH, Martinez G, Varghese A, Hoppe RT. Topical nitrogen mustard in the management of mycosis fungoides: update of the Stanfd experience. Arch Dermatol 23;139: Local radiation Wilson LD, Kacinski BM, Jones GW. Local superficial radiotherapy in the management of minimal stage IA cutaneous T-cell lymphoma (Mycosis Fungoides). International Journal of Radiation Oncology, Biology, Physics 1998;4: Topical bexarotene Breneman D, Duvic M, Kuzel T, et al. Phase 1 and 2 trial of bexarotene gel f skin directed treatment of patients with cutaneous T cell lymphoma. Arch Dermatol 22;138: Heald P, Mehlmauer M, Martin AG, et al. Topical bexarotene therapy f patients with refracty persistent early stage cutaneous T cell lymphoma: results of the phase III clinical trial. J Am Acad Dermatol 23;49: Tazarotene Gel Apisarnthanarax N, Talpur R, Ward S, Ni X, Kim HW, Duvic M. Tazarotene.1% gel f refracty mycosis fungoides lesions: an open-label pilot study. J Am Acad Dermatol 24;5:6-67. Topical imiquimod Deeths MJ, Chapman JT, Dellavalle RP, Zeng C, Aeling JL. Treatment of patch and plaque stage mycosis fungoides with imiquimod 5% cream. J Am Acad Dermatol 25;52: Phototherapy (UVB and PUVA) Gathers RC, Scherschun L, Malick F, Fivenson DP, Lim HW. Narrowband UVB phototherapy f early stage mycosis fungoides. J Am Acad Dermatol 22;47: Querfeld C, Rosen ST, Kuzel TM, et al. Long term follow up of patients with early stage cutaneous T cell lymphoma who achieved complete remission with psalen plus UV A monotherapy. Arch Dermatol 25;141: Total skin electron beam therapy ( TSEBT) Chinn DM, Chow S, Kim YH, Hoppe RT. Total skin electron beam therapy with without adjuvant topical nitrogen mustard nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol Biol Phys 1999;43: Ysebaert L, Truc G, Dalac S et al. Ultimate results of radiation therapy f T1-T2 mycosis fungoides. Int J Radiat Oncol Biol Phys 24;58: Continued on next page Note: All recommendations are categy 2A unless otherwise indicated. Version 4.211, 8/24/11 National Comprehensive Cancer Netwk, Inc. 211, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MFSS-A 2 of 4

11 NCCN Guidelines Version Systemic therapies Alemtuzumab f Sezary Syndrome ± lymph node disease Lundin J, Hagberg H, Repp R, et al. Phase 2 study of alemtuzumab (anti-cd52 monoclonal antibody) in patients with advanced mycosis fungoides/sezary syndrome. Blood 23;11: Bernengo MG, Quaglino P, Comessatti A, et al. Low-dose intermittent alemtuzumab in the treatment of Sezary syndrome: clinical and immunologic findings in 14 patients. Haematologica 27;92: Gautschi O, Blumenthal N, Streit M, et al. Successful treatment of chemotherapyrefracty Sezary syndrome with alemtuzumab (Campath-1H). Eur J Haematol 24;72: Retinoids Zhang C, Duvic M. Treatment of cutaneous T-cell lymphoma with retinoids. Dermatol Ther 26;19: Duvic M, Martin AG, Kim Y, et al. Phase 2 and 3 clinical trial of al bexarotene (Targretin capsules) f the treatment of refracty persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol 21;137: Duvic M, Hymes K, Heald P, et al. Bexarotene is effective and safe f treatment of refracty advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol.21;19: Interferon Olsen EA. Interferon in the treatment of cutaneous T-cell lymphoma. Dermatol Ther 23;16: Kaplan EH, Rosen ST, Nris DB, et al. Phase II study of recombinant human interferon gamma f treatment of cutaneous T-cell lymphoma. J Natl Cancer Inst 199;82: Vinostat Duvic M, Talpur R, Ni X, et al. Phase 2 trial of al vinostat (suberoylanilide hydroxamic acid, SAHA) f refracty cutaneous T-cell lymphoma (CTCL). Blood 27;19: Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of vinostat in patients with persistent, progressive, treatment refracty cutaneous T-cell lymphoma. J Clin Oncol 27;25: Duvic M, Olsen EA, Breneman D, et al. Evaluation of the long-term tolerability and clinical benefit of vinostat in patients with advanced cutaneous T-cell lymphoma. Clin Lymphoma Myeloma. 29;9: Romidepsin Piekarz RL, Frye R, Turner M, et al. Phase II Multi-Institutional Trial of the Histone Deacetylase Inhibit Romidepsin As Monotherapy f Patients With Cutaneous T- Cell Lymphoma. J Clin Oncol 29;27: SUGGESTED TREATMENT REGIMENS References Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refracty cutaneous T-cell lymphoma. J Clin Oncol 21; 28: Extracpeal photopheresis (ECP) Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracpeal photochemotherapy. Preliminary results. N Engl J Med 1987;316: Zic JA, Stricklin GP, Greer JP, et al. Long-term follow-up of patients with cutaneous T-cell lymphoma treated with extracpeal photochemotherapy. J Am Acad Dermatol 1996;35: Denileukin diftitox Olsen E, Duvic M, Frankel A, et al. Pivotal phase III trial of two dose levels of denileukin diftitox f the treatment of cutaneous T-cell lymphoma. J Clin Oncol 21;19: Prince HM, Duvic M, Martin A, et al. Phase III placebo-controlled trial of denileukin diftitox f patients with cutaneous T-cell lymphoma. J Clin Oncol 21;28: Methotrexate Zackheim HS, Kashani-Sabet M, Hwang ST. Low-dose methotrexate to treat erythrodermic cutaneous T-cell lymphoma: results in twenty-nine patients. J Am Acad Dermatol 1996;34: Zackheim HS, Kashani-Sabet M, McMillan A. Low-dose methotrexate to treat mycosis fungoides: a retrospective study in 69 patients. J Am Acad Dermatol 23;49: Liposomal doxubicin Wollina U, Dummer R, Brockmeyer NH, et al. Multicenter study of pegylated liposomal doxubicin in patients with cutaneous T-cell lymphoma. Cancer 23;98(5): Quereux G, Marques S, Nguyen J-M, et al. Prospective multicenter study of pegylated liposomal doxubicin treatment in patients with advanced refracty mycosis fungoides Sezary syndrome. Arch Dermatol 28;144: Gemcitabine Duvic M, Talpur R, Wen S, Kurzrock R, David CL, Apisarnthanarax N. Phase II evaluation of gemcitabine monotherapy f cutaneous T-cell lymphoma. Clin Lymphoma Myeloma 26;7(1): Marchi E, Alinari L, Tani M, et al. Gemcitabine as frontline treatment f cutaneous T-cell lymphoma: phase II study of 32 patients. Cancer 25;14(11): Zinzani PL, Baliva G, Magagnoli M, et al. Gemcitabine treatment in pretreated cutaneous T-cell lymphoma: experience in 44 patients. J Clin Oncol 2;18: Zinzani PL, Venturini F, Stefoni V, et al. Gemcitabine as single agent in pretreated T-cell lymphoma patients: evaluation of the long-term outcome. Ann Oncol 21;21: Continued on next page Note: All recommendations are categy 2A unless otherwise indicated. Version 4.211, 8/24/11 National Comprehensive Cancer Netwk, Inc. 211, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MFSS-A 3 of 4

12 NCCN Guidelines Version SUGGESTED TREATMENT REGIMENS References Systemic therapies continued Combination therapies Pentostatin Skin-directed + Systemic Cummings FJ, Kim K, Neiman RS, et al. Phase II trial of pentostatin in refracty lymphomas and cutaneous T-cell disease. J Clin Oncol 1991;9(4): Temozolomide Tani M, Fina M, Alinari L, Stefoni V, Baccarani M, Zinzani PL. Phase II trial of temozolomide in patients with pretreated cutaneous T-cell lymphoma. Haematologica 25;9(9): Btezomib Zinzani PL, Musuraca G, Tani M, et al. Phase II trial of proteasome inhibit btezomib in patients with relapsed refracty cutaneous T-cell lymphoma. J Clin Oncol 27;25(27): Low dose Pralatrexate Hwitz SM, Duvic M, Kim Y, et al. Pralatrexate is active in cutaneous T-cell lymphoma (CTCL): Results of a multicenter, dose-finding trial. ASH Annual Meeting Abstracts. 29;114:91. Liposomal doxubicin Quereux G, Marques S, Nguyen J-M, et al. Prospective multicenter study of pegylated liposomal doxubicin treatment in patients with advanced refracty mycosis fungoides Sezary syndrome. Arch Dermatol 28;144: Gemcitabine Awar O, Duvic M. Treatment of transfmed mycosis fungoides with intermittent low-dose gemcitabine. Oncology 27;73: Pralatrexate O'Conn O, Pro B, Pinter-Brown L, et al. PROPEL: Results of the pivotal, multicenter, phase II study of pralatrexate in patients with relapsed refracty peripheral T-cell lymphoma (PTCL). ASCO Meeting Abstracts. 29;27:8561. Romidepsin Piekarz R, Wright J, Frye R, et al. Final results of a phase 2 NCI multicenter study of romidepsin in patients with relapsed peripheral T-cell lymphoma (PTCL). ASH Annual Meeting Abstracts. 29;114: Denileukin diftitox Talpur R, Jones DM, Alencar AJ, et al. CD25 expression is crelated with histological grade and to denileukin diftitox in cutaneous T-cell lymphoma. J Invest Dermatol 26;126: Rupoli S, Goteri G, Pulini S, et al. Long term experience with low dose interferon alpha and PUVA in the management of early mycosis fungoides. Eur J Haematol 25;75(2): Kuzel TM, Roenigk HH Jr, Samuelson E, et al. Effectiveness of interferon alfa-2a combined with phototherapy f mycosis fungoides and the Sézary syndrome. J Clin Oncol 1995;13(1): McGinnis KS, Shapiro M, Vittio CC, et al. Psalen plus long wave UV A (PUVA) and bexarotene therapy: An effective and synergistic combined adjunct to therapy f patients with advanced cutaneous T cell lymphoma. Arch Dermatol 23;139(6): Wilson LD, Jones GW, Kim D, et al. Experience with total skin electron beam therapy in combination with extracpeal photopheresis in the management of patients with erythrodermic (T4) mycosis fungoides. Journal of the American Academy of Dermatology. 2;43(1):54-6. Stadler R, Otte H-G, Luger T, et al. Prospective randomized multicenter clinical trial on the use of interferon alpha -2a plus acitretin versus interferon alpha -2a plus PUVA in patients with cutaneous T-cell lymphoma stages I and II. Blood 1998;92: Systemic + Systemic Foss F, Demierre MF, DiVenuti G. A phase 1 trial of bexarotene and denileukin diftitox in patients with relapsed refracty cutaneous T cell lymphoma. Blood 25;16(2): Straus DJ, Duvic M, Kuzel T, et al. Results of a phase II trial of al bexarotene (Targretin) combined with interferon alfa 2b (Intron A) f patients with cutaneous T cell lymphoma. Cancer 27;19(9): Talpur R, Ward S, Apisarnthanarax N, Breuer Mcham J, Duvic M. Optimizing bexarotene therapy f cutaneous T cell lymphoma. J Am Acad Dermatol. 22;47(5): Suchin KR, Cucchiara AJ, Gottleib SL, et al. Treatment of cutaneous T-cell lymphoma with combined immunomodulaty therapy: a 14-year experience at a single institution. Arch Dermatol. 22;138(8): Richardson SK, Lin JH, Vittio CC, et al. High clinical rate with multimodality immunomodulaty therapy f Sezary syndrome. Clin Lymphoma Myeloma 26;7: Note: All recommendations are categy 2A unless otherwise indicated. Version 4.211, 8/24/11 National Comprehensive Cancer Netwk, Inc. 211, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MFSS-A 4 of 4