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CTCL Treatment Algorithms How I Treat Advanced Stage CTCL

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CTCL Treatment Algorithms How I Treat Advanced Stage CTCL CTCL Treatment Algorithms How I treat advanced stage CTCL Francine Foss MD Professor of Medicine Hematology and Bone Marrow Transplantation Yale University School of Medicine New Haven, CT USA DISCLOSURES • SEATTLE GENETICS, SPECTRUM- consultant, speaker • MIRAGEN- consultant • MALLINRODT- consultant • KYOWA – investigator, consultant WHO-EORTC Classification of Cutaneous T-cell and NK Lymphomas- Incidence in US by SEER Registry Data Mycosis fungoides MF variants and subtypes (3836) Folliculotropic MF Pagetoid reticulosis Granulomatous slack skin Sézary syndrome (117) Adult T-cell leukemia/lymphoma Primary cutaneous CD30+ lymphoproliferative disorders (858) 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, pleomorphic (1840) Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional) Cutaneous γ/δ T-cell lymphoma Willemze R, et al. Blood. 2005;105:3768-3785. Skin manifestations and outcomes Patches, papules and T1 plaques covering < 10% of the skin T1 surface Patches, papules or T2 plaques covering ≥ T3 10% of the skin surface Tumors (≥ 1) T3 T2 Confluence of T4 erythematous lesions covering ≥ 80% BSA Skin stage 10 Yr relative survival T4 T1 100 % T2 67 % T3 39 % T4 41 % *Observed/expected survival x 100 for age-, sex-, and race- matched controls Zackheim HS, et al. J Am Acad Dermatol. 1999;40:418-425. Revisions to TNMB Classification, ISCL/EORTC Consensus Document T (Skin) N (Nodes) T1 Limited patch/plaque N0 No clinically abnormal LNs (< 10% of total skin surface) N1 Clinically abnormal LNs; histopath T2 Generalized patch/plaque Dutch Gr 1 or NCI LN0-2 (clone +/-) (> 10% of total skin surface) N2 Clinically abnormal LNs; histopath T3 Tumors Dutch Gr 2 or NCI LN 3 (clone +/-) T4 Generalized erythroderma N3 Clinically abnormal LNs; histopath Dutch Gr 3-4 or NCI LN4 (clone +/-) Nx Clinically abnormal LNs, no histo info M (Viscera) B (Blood) M0 No visceral involvement B0 No significant blood involvement M1 Visceral involvement B1 Low blood tumor burden B2 High blood tumor burden ISCL=International Society for Cutaneous Lymphomas; LN=lymph node; TNMB=(T), lymph nodes (N), visceral involvement (M), and blood (B) staging criteria Reference: 1. Olsen, et al. Blood. 2007;110:1713-1722. 5 TNMB Classification and Staging for MF/SS, ISCL/EORTC Consensus Document Clinical Stages TNM Classification IA T1 N0 M0 B0-1 IB T2 N0 M0 B0-1 IIA T1 - 2 N1-2 M0 B0-1 IIB T3 N0-2 M0 B0-1 IIIA T4 N0-2 M0 B0 IIIB T4 N0-2 M0 B1 IVA1 T1 - 4 N0-2 M0 B2 IVA2 T1 - 4 N3 M0 B0-2 IVB T1 - 4 N0-3 M1 B0-2 Reference: 1. Olsen, et al. Blood. 2007;110:1713-1722. 6 Disease-Specific Survival by Clinical Stage . 1,398 patients with MF 100 Retrospective, 525 patients . 104 patients with SS US 80 60 40 UK 20 Probability Probability of Survival (%) Kim YH, et al. Arch Dermatol. 2003;139:857-66. 0 0 10 20 30 Time Since Diagnosis (yrs) Agar NS, et al. J Clin Oncol. 2010;28:4730-4739. 7 My Staging Evaluation for MF/SS • Physical Exam • Skin extent & type, photodocumentation • LN, organomegaly/masses • Laboratory studies • CBC , LDH, metabolic panel • Flow cytometry: CD3, CD4, CD7, CD8, CD26 to assess for ↑CD4+, CD4/CD8 or abnormal phenotype (CD7- or CD26-) • VBeta panel by flow cytometry to identify clone(s) • T cell gene rearrangement and FISH for CTCL panel • HTLV-1 if risk factors • Imaging studies • whole body PET/CT or CT with contrast • MRI if appropriate • Biopsy of suspicious LNs (>2 cm or sig. PET+) or suspected visceral involvement. Core needle or excisional Image courtesy of A.Moskowitz, MD with image permissions • Bone marrow biopsy if B2 or clinical suspicion 8 • 161 patients at Yale who had Vbeta analysis studied • 34 had B2 by flow cytometry • Vbeta detected 25 of 34 (73%) • 12 of the 127 B1 patients had Vbeta positivity, 10 of these had +TCRR Prognostic Factors for Early Stage Patients from CLIPi Prognostic factors associated with OS • Age >60 • Male sex • Presence of plaques • Folliculotropic • LN stage N1/Nx Low risk: 0-1 RF (10 yr OS 90.3%) Intermediate risk: 2 RF (10 yr OS 76.2%) High risk: 3-5 RF (10 yr OS 48.9%) LN=lymph node; OS=overall survival Reference: 1. Benton EC, et al. European J Cancer. 2013;49:2859-2868. 11 Prognostic factors for advanced stage: CLIC Retrospective Study Prognostic Factors associated Low risk = zero to one variable; with OS Intermediate risk = two variables • Stage IV High risk = three to four variables • Elevated LDH • Age > 60 • Large Cell transformation in skin Julia J. Scarisbrick et al. JCO 2015;33:3766-3773 Clinical Approach By Stage T1: Limited T2: Generalized T4: patch/plaque patch/plaque T3: Tumor Erythroderma (<10% BSA) (≥10% BSA) N0: Nodes clinically uninvolved M0 IA IB IIIA IIB N1: Nodes enlarged, Folliculotrophic type histologically uninvolved M0 IIA IIIB N2-3: Nodes clinically Large Cell Transformation unilesional normal (N2) or enlarged (N3), histologically M0 IVA involved Large Cell Transformation visceral site or node N0-3: Visceral M1 involvement Sezary with high risk genetics/cytogeneticsIVB B0: Absence of significant peripheral blood Sézary cells B1: Low tumor burden that-Others does not meet the criteria of B2 cells B2: Significant peripheral blood >1000/μL Sézary cells with positive clone = Early-stage disease = Advanced disease 1. Olsen E, et al. Blood. 2007;110:1713-1722. 13 2. Lansigan F and Foss FM. Drugs 2010;70:273-86. Current status of treatment in a nutshell • MF is an immunologically responsive disease • Most new approved therapies have CR rate (≤ 10%) and 30% Risk for progression in 525 ORR (PR + CR) patients • Most patients require multiple therapies over the course of their disease and often treatments are repeated • Many patients receive combinations of agents and both systemic and topical therapy • Stable disease is a meaningful endpoint for patients if relief of pruritus and skin symptoms • Infections are a major cause of morbidity and mortality Kim YH, et al. Arch Dermatol. 2003;139:857-866. Stage-based Approach to Treatment IA IB/IIA IIB III IV Limited Generalized Tumors Erythroderma Extracutan patch/plaque patch/plaque disease Topical steroid, retinoid (bex), NM phototherapy, local RT, imiquimod Photopheresis bexarotene or IFN Alemtuzumab Precision TSEBTmedicine + ECP, IFN Checkpoint therapies and other novelCombination approachimmunomodulatoryBexarotene, methotrexate, approaches IFNchemo vorinostat, romidepsin New targeted or cytotoxic systemic therapy** Allo-HSCT Clinical Trials ECP=extracorporeal photopheresis **Brentuximab vedotin, pralatrexate, liposomal doxorubicin, gemcitabine, other This slide represents expert opinion, no source reference is available 15 Extensive Patch/Plaque Disease Treatment Options • Low dose total skin (12 Gy) • Phototherapy (± retinoids, IFN, ? vorinostat) • ECP with retinoids, IFN, HDAC • Systemic therapies start with oral agents • (bexarotene. Vorinostat, methotrexate), then progress to IV agents- romidepsin, gemcitabine, pralatrexate, etc Key Point • Combine topical with systemic therapies, try biologics first • Address quality of life issues • Oral antibiotics for superinfection • Maintenance is necessary Management of Tumor Stage MF Treatment Options • Important to know if LCT or CD30+ • Local radiotherapy for immediate palliation • Systemic therapies: oral and IV, brentuximab if CD30+ • May require more aggressive multi-agent chemotherapy to debulk (Gem Doxil or Gem Ox or other regimens, EPOCH) • For multiple tumors, aggressive clinical features, high LDH, consider stem cell transplant after remission is achieved Key Points • Outcomes poor for most with multiple tumors • May have large cell transformation • Maintenance is necessary if patient not going to transplant • Think about transplant earlier in course of disease NCCN Guidelines for Tumor Stage MF Treatment of Large Cell Transformation Kaplan–Meier Estimates of Survival With Different Systemic Therapies for Large Cell Transformation MF with LCT included in PROPEL trial of pralatrexate, FDA approved Talpur et al, Clinical Lymphoma Myeloma and Leukemia, Volume 16, Issue 1, 2016, 49–56 Management of Erythroderma/Sezary Syndrome • • ECP +/- immunomodulators • Interferon-alfa (IFN-α) • Bexarotene or other retinoid • Methotrexate (≤ 50 mg/week) • HDAC inhibitors- romidepsin, vorinostat • Mogamulizumab (if FDA approved) • Campath subcutaneous • Gemcitabine combos, other combo chemotherapy • Antibiotics as needed • Avoid central lines due to risk of sepsis • Most patients need acyclovir and PCP prophylaxis NCCN treatment recommendations for Stage III patients Extracorporeal Photopheresis -Combining biological agents is most effective approach Fig. 1. Estimated pooled response rates for patients with SS to ECP monotherapy, ECP + IFN alfa or gamma, and ECP + IFN + bexarotene capsules (Bex). N = number of patients extracted from the literature with a clear definition of SS and an overall response rate... Zic et al, Dermatologic Clinics, Volume 33, Issue 4, 2015, 765–776 NCCN Guidelines for Stage IV Mycosis Fungoides FDA approved agents for CTCL Efficacy data Agent (Class) Indication Study N ORR DOR Patients with CTCL Romidepsin Pivotal 96 34% 15 mo who have received systemic therapy Supportive 71 35% 11 mo Denileukin diftitox Tumors that express Pivotal 71 30% 4 mo (Fusion protein) CD25 Bexarotene Cutaneous (Retinoid x-receptor Pivotal 62 32% 5+ mo manifestations activator) Cutaneous Vorinostat Pivotal 74 30% 6+ mo manifestations
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