Treatment of Cutaneous TCell Lymphoma Focus on RelapsedRefractory

Treatment of Cutaneous T-Cell Lymphoma: Focus on Relapsed/Refractory Disease This program is supported by an educational grant from Ligand Clinical Care Options, LLC

Treatment of Cutaneous T-Cell Lymphoma: Focus on Relapsed/Refractory Disease Pathophysiology and Treatment John A. Zic, MD Vanderbilt University Medical Center Nashville, Tennessee Diagnosis and Staging Timothy M. Kuzel, MD Northwestern University Chicago, Illinois

Focus on Relapsed/Refractory Disease First Description of Mycosis Fungoides clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Primary Cutaneous T-Cell Lymphoma (CTCL) § Mycosis fungoides (MF) – Most common T-Cell lymphoma of the skin – Isolated patches, plaques, and/or tumors § Classic histopathologic features – Superficial dermal infiltrate of malignant lymphocytes – Cerebriform nuclei within malignant lymphocytes – Epidermotropism (Pautrier’s microabscesses) – Early stage lesions include reactive benign T-lymphocytes clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Histopathologic Appearance of MF § Upper dermal infiltrate of small lymphocytes with presence of Pautrier’s microabscesses in epidermis clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease TNM and B Staging of MF* § T (Skin) § M (Viscera) – T 1 Limited patch/plaque (< 10% BSA) – M 0 No visceral involvement – T 2 Generalized patch/plaque – M 1 Visceral involvement – T 3 Tumors § B (Blood) – T 4 Generalized erythroderma * Staging should be done at diagnosis only and does not change with treatment effect; provides prognostic information for patients. – B 0 Atypical circulating cells not present (< 5%) – B 1 > 5% atypical cells, < 1000 atypical cells/mm 3 – B 2 > 1000 atypical cells/mm 3 clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease TNM and B Staging of MF (continued) § N (Nodes) – N 0 No clinically abnormal nodes – N 1 Clinical abnormal node – N 2 Biopsy performed, not involved with MF – N 3 Biopsy performed, involved with MF – LN 3 large clusters of atypical cells (> 6 cells/cluster) to partial effacement – LN 4 lymph node effacement – LN 0 normal; LN 1 dermatopathic reactive lymph node – LN 2 dermatopathic node with atypical cells (< 6 cells/cluster) clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease CTCL Staging: T 1, T 2 skin stages § Approximately 50% to 70% of patients with MF/Sézary syndrome will present with isolated patches or plaque type lesions T 1 Kim, Y. H. et al. Arch Dermatol 2003; 139: 857 -866 T 2 clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease CTCL Staging: T 3 Tumor Stage § Tumors commonly observed with progression from earlier stages – Rarely present at initial diagnosis clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease CTCL Staging: T 4 Skin Stage § MF/Sézary syndrome; generalized erythroderma § Exfoliative erythroderma – Significant peripheral blood involvement in > 90% of patients with erythroderma – Disabling pruritus Sausville EA, et al. Ann Intern Med. 1988; 109: 372 -382. Schester GP, et al. Blood. 1987; 69: 1 -9. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease CTCL Staging: T 4 Skin Stage (continued) § Poor prognostic features – PAS-positive cytoplasmic inclusions – CD 4 positive, CD 7 negative phenotype – Large circulating Sézary cells clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Staging of CTCL: LN Path stages clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Clinical Staging for MF TNM Classification* Clinical Stages T N M IA T 1 N 0 M 0 IB T 2 N 0 M 0 IIA T 1 -T 2 N 1 M 0 IIB T 3 N 0 -1 M 0 IIIA T 4 N 0 M 0 IIIB T 4 N 1 M 0 IVA T 1 -4 N 2 -3 M 0 IVB T 1 -4 N 0 -3 M 1 * The “B” classification does not alter the clinical stage. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease CTCL: Survival By Stage § Survival for CTCL patient varies according to stage § Little overlap in survival between stages – Stage IA: no median survival, similar to general population – Stage IB: 5 -year survival ~ 85% § Poor survival in advanced disease – Median survival for patients with stage IV CTCL: ~ 2. 5 years Kim, Y. H. et al. Arch Dermatol 2003; 139: 857 -866 clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease MF Histopathology § Surface antigen immunophenotyping – Classic antigenic profile: CD 4+, CD 8 -, CD 26 -, CD 45 RO+ – Variable presence or loss of pan T-cell markers CD 5 and/or CD 7 § Early-stage lesions characterized by – Infiltrating “reactive” CD 8+ T-lymphocytes – Cutaneous dendritic cells (lost upon disease progression) § T-cell gene rearrangement testing to confirm clonality clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease MF: Recommended Staging Studies § Routine clinical evaluations should include: – History and physical examination – Complete blood count with differential – Examination of blood smear for quantification of atypical lymphocytes (Sézary cells) – Comprehensive chemistry panel – Lactate dehydrogenase (LDH) – Lymph node biopsy if clinically apparent nodes present clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease MF: Other Staging Studies § Other studies performed in special circumstances or for clinical trials § Bone marrow aspirate/biopsy – Involvement in patients with advanced disease rarely changes treatment recommendation § Imaging Studies (CT scans) – Generally of modest utility and rarely positive in early T 1 or T 2 disease – Reserved for patients with Sézary syndrome or for quantifying disease stage in patients with tumor stage and palpable adenopathy clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Differential Diagnosis of MF § It is important to distinguish between MF and other T-cell disorders involving the skin – CD 30+ cutaneous large T-cell lymphoma – CD 30 - cutaneous large T-cell lymphoma – Peripheral T-cell lymphoma (unspecified) – Lymphomatoid papulosis – Subcutaneous panniculitis-like T-cell lymphoma clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease WHO/EORTC Classification of Primary CTCL, NK-cell Lymphomas MF/MF variants and subtypes Folliculotropic MF Pagetoid reticulosis Granulomatous slack skin Sézary syndrome Adult T-cell leukemia/lymphoma Primary cutaneous CD 30+ lymphoproliferative disorders Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis Subcutaneous panniculitis-like T-cell lymphoma Extranodal NK/T-cell lymphoma, nasal type Primary cutaneous peripheral T-cell lymphoma, unspecified Primary cutaneous aggressive epidemiotropic CD 8+ T-cell lymphoma (provisional) Cutaneous γ/δ T-cell lymphoma (provisional) Primary cutaneous CD 4+ small/medium-sized pleomorphic T-cell lymphoma (provisional) Willemze R, et al. Blood. 2005; 105: 3768 -3785. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Pathogenesis of MF Skin homing T cells clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Membrane Proteins of the Malignant T Cell CD 3 and T-cell receptor CD 4 (TH 2 subtype) CD 45 RO (Memory T Cell) LFA-1 CCR 4 CD 26 (-)/(+) CLA (Cutaneous Lymphoid Antigen) CD 7 (-)/(+) CD 25 (+)/(-) clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Pathogenesis of MF CCR 4 αEβ 7 Pautrier’s microabscess E-selectin Endothelial cell TCR CCL 22 CD 4 E-cadherin Langerhans’ cell MHC-II Epidermis Epidermotropism CLA CCR 4 T cell CCL 17 Dermis Capillary Extravasation Girardi M et al. N Eng J Med. 2004; 350: 1978 -1988. Copyright © 2004 Massachusetts Medical Society. All rights reserved. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease CTCL: Prognostic Groups § Low-risk group (most favorable): TNM stages IA, IB, IIA. – Survival: ~ 12 years § Intermediate risk group: TNM stages IIB, III, IVA with grade LN 3 lymph node histopathology – Survival: ~ 2 -3 years § High-risk group (least favorable): TNM stage IVB, IVA with grade 2 years LN 4 lymph node histopathology – Survival: ~ < 2 years Foss FM, Sausville EA. Hematol Oncol Clin North Am. 1995; 9: 1011 -1019. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease CTCL: Skin-Directed Therapy § Topical steroids § Topical nitrogen mustard (NM) – Mechlorethamine § Phototherapy – NBUVB – PUVA § Radiotherapy § Topical bexarotene gel – Total skin EBRT § Topical carmustine – Localized EBRT clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease CTCL: Systemic Therapy § Tretinoin capsules § Bexarotene capsules § Acitretin capsules § Methotrexate § Prednisone/chlorambucil § Extracorporeal photochemotherapy § Other biologic modifiers § Denileukin diftitox § Combination chemotherapy § Interferon clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease CTCL Treatment Algorithm Stage IA Stage IB, IIA Stage IIB Stage III Stage IVA, B Topical corticosteroids (Class I) Photopheresis ± IFN ± Bexarotene gel PUVA (± IFN or ± Retinoid) Electron Beam Bexarotene capsules Denileukin Diftitox Nitrogen Mustard UVB Photopheresis Chemotherapy or Allo. SCT clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease CTCL: Topical Therapies clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Topical Nitrogen Mustard for MF § Mechanism of action: DNA alkylation, possible delayed type hypersensitivity (TH 1) response § Aqueous or ointment base, applied to skin once daily – Continue for 2 -3 months after CR (longer maintenance does not decrease relapse rate) § Efficacy in patch/plaque stage MF – T 1 (n = 107) OR 93%; CR 65%; 5 -year relapse free rate, 52% – T 2 (n = 88) OR 72%; CR 34%; 5 -year relapse free rate, 19% Kim YH. Dermatol Ther. 2003; 16: 288 -298. Kim YH, et al. Arch Dermatol. 2003; 139: 165 -173. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Topical Nitrogen Mustard for MF § Adverse effects – Irritant dermatitis < 25% (ointment) – Allergic contact dermatitis < 66% (aqueous), < 10% (ointment) – No systemic absorption – Possible slight increase in nonmelanoma skin cancers Kim YH. Dermatol Ther. 2003; 16: 288 -298. Kim YH, et al. Arch Dermatol. 2003; 139: 165 -173. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Topical Bexarotene for MF § Mechanism of action: Specific retinoid X receptor ligand that influences critical pathways for cell proliferation, differentiation, and apoptosis § Formulation: 1% gel, applied to affected skin, 1 -2 cm margins – Applied every other day first week, once daily second week, up to 4 times daily as tolerated § Adverse effects – Irritant “retinoid” dermatitis, 70% – Intervene with dose reduction, mildly potent topical steroids Zhang C, Duvic M. Dermatol Ther. 2003; 16: 322 -330. Kempf W, et al. Hematol Oncol Clin N Am. 2003; 17: 1405 -1419. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Topical Bexarotene For MF § Efficacy in patch/plaque stage MF: – Phase I-II trial (n = 67): OR 63%, CR 21% – Previously untreated patients, OR 75% – Previously treated patients, OR 67% – Median onset of response, 5 mos – Median duration of response, ~ 25 mos – Phase III trial (n = 50), refractory IA, IB, IIA patients: OR 44%, CR 8% Breneman et al. Arch Dermatol. 2002; 138: 325 -332. Heald et al. J Invest Dermatol. 2000; 114: 840 [Abstract 545]. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Phototherapy for MF § Mechanism of action: induction of T-cell apoptosis, possibly Langerhans’ cell apoptosis – Wide-band UVB (WBUVB) – Narrow-band UVB (NBUVB) – Psoralens + UVA = PUVA UVB 290 nm UVA 320 nm 400 nm Narrow-band UVB 311 nm Baron ED, Stevens SR. Dermatol Ther. 2003; 16: 303 -310. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Phototherapy for MF: Administration § WBUVB: 3 X weekly 50– 200 milijoules/cm 2 § NBUVB: 2 -3 X weekly 1– 4 joules/cm 2 § PUVA: 2 -3 X weekly 1– 8 joules/cm 2 + 0. 4 mg/kg psoralens (8 -MOP) PO 1 hr before treatment Baron ED, Stevens SR. Dermatol Ther. 2003; 16: 303 -310. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease PUVA in MF § Efficacy § Adverse Effects – IA: 54/60 (90% CR), 31% relapse – Phototoxic sunburn reactions – IB: 88/116 (76% CR), 56% relapse – Nausea from ingested psoralens – IIA: 7/9 (78% CR), 71% relapse – Increased risk SCC > BCC (8% to 10% with PUVA) – III: 11/18 (61% CR), ~ 100% relapse – Increased risk of melanoma (seen in psoriasis pts treated with PUVA 15 years after first exposure) Baron ED, Stevens SR. Dermatol Ther. 2003; 16: 303 -310. Herrmann JJ, et al. J Am Acad Dermatol. 1995; 33: 234 -242. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease EBRT for MF § Total skin EBRT – – 6 -9 Me. V electrons via linear accelerator 6 field technique: ant, post, 4 oblique fields 1. 5 -2. 0 Gy per fraction over 9 -10 wks Total dose: 30 -36 Gy § Localized EBRT – Tumors: 9 -12 Me. V with 2 cm margins – Total dose: 20 -30 Gy § Method of action: targets lymphocytes, most radiosensitive cell Hoppe RT. Dermatol Ther. 2003; 16: 347 -354. Jones GW, et al. Hematol Oncol Clin N Am. 2003; 17: 1421 -1434. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Total Skin EBRT Efficacy (n = 561 combined analysis, OR rates 100%) Stage CR, % Relapse free, % (2. 5 yrs) IA 84 -96 64 -73 IB 56 -81 35 -40 ll. A 63 -74 21 -37 ll. B 24 -53 7 -26 lll 26 -50 10 -23 15 -year progression free survival Early disease (IA, IB, IIA) ~ 25% Late disease (IIB, III, IV) < 10% Hoppe RT. Dermatol Ther. 2003; 16: 347 -354. Jones GW, et al. Hematol Oncol Clin N Am. 1995; 9: 1057 -1076. Jones GW, et al. Hematol Oncol Clin N Am. 2003; 17: 1421 -1434. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Total Skin EBRT § Adverse effects – Acute skin effects: burning erythema, edema – Chronic skin effects: xerosis, superficial atrophy, telangiectasia, dyspigmentation – Alopecia, loss of nails (usually regrow) – Heat intolerance due to the suppression of sweat gland production (usual duration, 6 -12 mos) – Increased SCC and BCC – Otherapies may play a role Hoppe RT. Dermatol Ther. 2003; 16: 347 -354 Jones GW, et al. Hematol Oncol Clin N Am. 2003; 17: 1421 -1434. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease CTCL: Systemic Therapies clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Oral Retinoids for MF/Sézary Syndrome § Specific retinoid receptor ligands that influence critical pathways for cell proliferation, differentiation, and apoptosis Retinoid Daily Dose Acitretin 25 -50 mg/d Bexarotene* 300 mg/m 2 BSA/day Isotretinoin 1 mg/kg/d * FDA-approved for CTCL in December 1999 Zhang C, Duvic M. Dermatol Ther. 2003; 16: 322 -330. Kempf W, et al. Hematol Oncol Clin N Am. 2003; 17: 1405 -1419. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Oral Bexarotene in CTCL Oral Bexarotene Monotherapy in CTCL Reference Patients (n) ORR, % CR, % PR, % Heald P, 2000 4 100 Duvic M et al, 2001 94 45 Stage I, IIA* 54 Stage ≥ IIB† 45 Prince HM et al, 2001 7 71 Talpur R et al, 2002 54 48 4 * Relapse rate: 28% † Median time to relapse: 43 weeks Kempf W, et al. Hematol Oncol Clin N Am. 2003; 17: 1405 -1419. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Oral Bexarotene in CTCL (continued) Baseline Week 12 Week 28 clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Oral Bexarotene for MF/Sézary Syndrome § Adverse effects: hyperlipidemia (> 80%): usually requires treatment with lipid lowering agent – Triglyceride level of 700 -900 mg/d. L in patients on treatment warrants therapy interruption for 5 -7 days – Addition of lipid-lowering agent; resume therapy at half initial dose, monitor triglycerides once weekly thereafter – Initiation of lipid-lowering agent recommended 1 week before starting oral bexarotene – Diet: reduction of fat/sugar intake – Initiating with low-dose bexarotene feasible in some patients (eg, those with diabetes) Zhang C, Duvic M. Dermatol Ther. 2003; 16: 322 -330. Kempf W, et al. Hematol Oncol Clin N Am. 2003; 17: 1405 -1419. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Oral Bexarotene for MF/Sézary Syndrome § Other adverse effects: – Leukopenia (11%) – Central hypothyroidism (30% to > 70%): may require thyroid supplementation – Gemfibrozil contraindicated Zhang C, Duvic M. Dermatol Ther. 2003; 16: 322 -330. Kempf W, et al. Hematol Oncol Clin N Am. 2003; 17: 1405 -1419. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Stage IV Disease/Sézary Syndrome clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Sézary Syndrome § Characterized by erythroderma, circulating Sézary cells, adenopathy – Secondary characteristics: alopecia, onychodystrophy, palmar/plantar keratoderma § EORTC suggests: TCRR (+) peripheral blood, CD 4/CD 8 > 10 for diagnosis of Sézary syndrome. § Prognosis poor: median survival, < 20 -36 mos clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Photopheresis Whole Blood Ultraviolet A 8 -methoxypsoralens RBC WBC Return to Pt. Photoactivation Return to Pt. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Photopheresis for MF/Sézary Syndrome § CTCL protocol: one 3 -hour treatment on 2 consecutive days, every 4 weeks § Proposed mechanism of action – Induces apoptosis of lymphocytes – Converts monocytes to immature dendritic cells – Dendritic cells engulf lymphocytes and present tumor antigen to cytotoxic T cells Zic JA. Dermatol Ther. 2003; 16: 337 -346. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Photopheresis for MF/Sézary Syndrome Stage Total Patients OR, % CR, % IB 25 64 28 IIA 25 56 24 IIB 19 53 26 III 28 36 18 IVA 86 51 20 IVB 11 27 9 Skin stage T 1 7 57 43 Skin stage T 2 68 62 28 Skin stage T 3 44 32 16 Skin stage T 4 224 58 15 Sézary syndrome 105 43 10 Zic JA. Dermatol Ther. 2003; 16: 337 -346. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Denileukin Diftitox for CTCL § Diphtheria toxin fragments A and B linked to interleukin-2 – Approximately 50% CTCL tumor cells express interleukin-2 receptor § Pivotal study (N = 71) in pretreated patients, most with stage IIB-IVB disease (63%) – 30% overall response – Median duration of response, 4 mos Olsen E, et al. J Clin Oncol. 2001; 19: 376 -388. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Denileukin Diftitox for CTCL: Adverse Events § Acute hypersensitivity reactions (69%): acute; hypotension, SOB, rash, chest pain – Pretreatment with steroids may improve tolerability, maintain response § Vascular leak syndrome (27%): delayed; hypotension, edema, hypoalbuminemia § Infections (48%) § Lymphopenia (34%) Olsen E, et al. J Clin Oncol. 2001; 19: 376 -388. Foss FM et al. Clin Lymphoma. 2001; 4: 298 -302. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Chemotherapy for CTCL § Modest response, reserved for relapsed or refractory disease § Duration of response < 6 mos § Some agents show notable activity: – Deoxycoformycin – Gemcitabine: phase II trial (N = 32) untreated CTCL, 7 (22%) CR, 17 (53%) PR – Pegylated liposomal doxorubicin: retrospective analysis (N = 34) CTCL patients, 15 CR (DFS 13. 3 mo), 15 PR Kuzel TM. Dermatol Ther. 2003; 16: 355 -361. Pichardo DA, et al. Leuk Lymphoma. 2004; 45: 1755 -1765. Marchi E, et al. Cancer. 2005; 104: 2437 -2441. Wollina U, et al. Cancer. 2003; 98: 993 -1001. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Allogeneic Peripheral Stem Cell Transplant for CTCL Reference Patients (age, yrs) Conditioning Regimen GVHD prophylaxis Outcome Soligo 2003 N = 3 (51 -60) Fludarabine, TBI CSA, MMF 3 CR: 18 and 24 mo, 1 dead d+73 Molina 2003, 2005 N = 8 (21 -59) Fludar/Melph n = 4 Cyclophos/TBI n = 3 Cyclophos/Busulfan CSA n = 8 MTX n = 4 MMF n = 6 8 CR: 6 alive (33 -106 mo), 2 dead (sepsis) Guitart 2002 N = 3 (27 -39) Cyclophos/Mesna, TBI CSA, steroid, +/- MMF 3 CR: 15, 52, 60 mo Masood 2002 N = 1 (37) Cyclophos, TBI MTX, CSA CR: 24 mo Koeppel 1994 N = 1 (21) Cyclophos, TBI MTX, CSA, steroid CR: 72 mo Pichardo DA, et al. Leuk Lymphoma. 2004; 45: 1755 -1765. clinicaloptions. com/oncology

Focus on Relapsed/Refractory Disease Summary of Therapies for CTCL § Skin-directed therapies: highly effective in the early stages of MF – Relapses common § The challenge: develop systemic targeted therapies with minimal adverse effects capable of inducing meaningful remissions § Current therapeutic goal: do no harm, prevent disease progression § Comparison trials needed to prioritize systemic therapy clinicaloptions. com/oncology