Cutaneous Lymphomas New Aspects

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1 Cutaneous Lymphomas New Aspects Christiane Querfeld, MD, PhD Chief, Div. of Dermatology Director, Cutaneous Lymphoma Program City of Hope ~ How the Experts Treat Hematologic Malignancies Symposium March 21 23, 2019

2 Advisory Board Disclosures MiRagen, Trillium, Bioniz, Helsinn, Kyowa, Mallinckrodt Investigator Celgene, MiRagen, Trillium Therapeutics, Helsinn, Bioniz, Esai, Kyowa, Soligenix Funds/Research Grants Celgene

3 Cutaneous Lymphomas Diverse group of lymphoma Localized to the skin T-cell and B-cell types Mycosis fungoides and Sézary syndrome most common types

4 Epidemiology Most common between age of 50 to 60 years 6.4 per million people in the United States Male > female African American > Caucasian SEER data:

5 Etiology Unknown Some studies have shown links to Infectious Environmental Genetics

6 The 2018 Updated WHO-EORTC Classification of Hematologic Malignancies Mycosis fungoides Folliculotropic type Pagetoid reticulosis Granulomatous slack skin Sézary syndrome Primary cutaneous CD30+ lymphoproliferative disorders Lymphomatoid papulosis (type A-E, DUSP22-IRF4) Primary cutaneous anaplastic large cell lymphoma Subcutaneous panniculitis-like T cell lymphoma Cutaneous T cell lymphomas Primary cutaneous peripheral T cell lymphoma, rare subtypes Primary cutaneous γδ T cell lymphoma Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T cell lymphoma Primary cutaneous acral CD8+ T cell lymphoma (provisional) CD4 + small/medium-sized pleomorphic T-cell lymphoproliferative disorder (provisional) Primary cutaneous peripheral T cell lymphoma, NOS Extranodal NK/T cell lymphoma, nasal type Chronic active EBV infection Willemze et al. Blood 2019; Swerdlow et al. Blood 2016

7 CTCL The problems: Rare Not known by many physicians Mistaken for common skin rashes Diagnosis may take up to years Multiple skin biopsies may be needed Wounds Infections Complications from therapy

8 Mycosis fungoides can mimic other skin conditions Other skin conditions can mimic mycosis fungoides

9 Psoriasis Eczema Ringworm Contact allergy Drug-rash Mycosis fungoides: The great imitator Zackheim et al. JAAD 2002

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11 CD8+ 32 year-old female 10-year history of hypopigmented patches on extremities. Patches remained flat, now development of widespread patches. Previous tx with topical steroids on and off PMH: HTN, asthma The patient was referred for an aggressive cytotoxic CD8+ lymphoma CD3+CD4-CD8+ BF1+ with variable TIA1 expression and loss of CD7

12 How do we make a diagnosis? Clinical appearance Skin biopsies Additional tests Special histologic stains for phenotype (surface markers) Molecular tests (PCR, southern blot)

13 2 1 Characteristic histology 1.Upper-dermal band-like lymphocytic infiltrate with atypical lymphocytes 2.Epidermotropism 3.Pautrier s microabscesses 3

14 CTCL No single perfect test Biopsy Untreated skin Repeat biopsy if not diagnostic Determine lymphoma subtype

15 Prototype of CTCL Low-grade lymphoma Mycosis Fungoides Post-thymic T-cell malignancy (CD4 + /CD45RO + ) Malignancy of 3 different T-cell populations: Features of T-regulatory (CD25+FoxP3+), Th 2 - and Th 17 -cell phenotype Th2-driven immunosuppressive properties Secretion of IL-4, IL-5, IL-6, IL-10 Peripheral eosinophilia, elevated IgE Decreased antigen-specific T-cell response Impaired cell mediated cytotoxicity Patch, plaque, tumors and erythroderma Berger C et al. 2005; Dummer R et al. 1996; Krejsgaard T et al. 2010

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17 Folliculotropic MF

18 Sézary Syndrome Systemic and aggressive variant Exfoliative erythroderma Ectropion, alopecia, palmoplantar keratoderma Severe pruritus Circulating, atypical, malignant T-lymphocytes (Sézary cells)

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20 CTCL Staging All patients Physical exam Skin burden, nodes Skin biopsy Immunophenotyping TCR analysis CBC, CMP, LDH Selected patients Sézary cell counts by flow cytometry CD4+/CD7-; CD4+/CD26- CD4:CD8 ratio Molecular analysis/tcr sequencing HTLV-1 titer PET/CT scans Lymph node biopsy Bone marrow biopsy

21 CTCL - Prognosis What about cure? What means remission? What happens if the lymphoma comes back? What happens if the lymphoma progresses? How long will I live?

22 Most subtypes are indolent Chronic course Relapses are common Early stages have good prognosis

23 Skin manifestations of CTCL at diagnosis Stage at diagnosis T1: Patches/plaques covering <10% of body surface T2: Patches/plaques covering 10% of body surface Patients at diagnosis 42% 30% T3: Tumor(s) 15% T4: Erythroderma 12% Querfeld C & Rosen ST in Abeloff s Clinical Oncology, 2013

24 Disease-specific Survival according to (A) Clinical Stage and (B) T Classification Risk of Progression T-stage Elevated LDH Folliculotropic MF Peripheral blood clone Large cell transformation Tumor distribution Agar NS et al. J Clin Oncol by American Society of Clinical Oncology

25 Cutaneous T Cell Lymphoma Clinical Features Malignant Cells Micro-environment Prognostication What are the key findings that can help guide clinical management of cutaneous lymphomas? Management

26 Stage-based Treatment Algorithm for Mycosis Fungoides and Sézary Syndrome mogamulizumab

27 Systemic Agents Approved in CTCL Agent (class) Dosage Toxicity N Stage ORR DOR Extracorporeal photopheresis Denileukin diftitox (fusion protein) (E7777 currently in clinical trial) Bexarotene (retinoic X-receptor agonist) Vorinostat (class I/II HDAC inhibitor) Romidepsin (pan HDAC inhibitor) Brentuximab vedotin (CD30 Ab linked to antimicrotubule agent MMAE) Mogamulizumab (CCR4 Ab) 2 consecutive days/month 18ug/kg/day IV x 5 days q3weeks 300mg/m 2 /daily PO 400mg daily PO 14mg/m 2 / IV 1, 8, 15 q month 1.8 mg/kg IV infused over 30 minutes q3weeks (1.0 mg/kg) weekly x 4 w, then q2weeks - 32 Advanced stages Increased LFTs Capillary leak syndrome Hypothyroidism Hyperlipidemia Cytopenia Asthenia Diarrhea Cytopenia Asthenia Cytopenia Peripheral Neuropathy Fatigue Neutropenia Nausea Chills Skin rash 84% (skin) NR 71 IB-IVA 30% 4 m 62 IIB-IVA 32% 5 m 74 IB-IVB 30% 6 m (MF) 16 (palcl) 38 (17 SS) 186 IB-IVA 34% 35% IB-IVB IB-IVB 70% 65% 75% IB-IVA 28.6/47% 28% /37% 15 m 11 m 5 m 15.1 m 10.4 m 14 m

28 Treatment Principles Early stage Potential for cure Skin-directed therapies, combination therapies Advanced stage Palliation and control of disease Multidisciplinary approach Systemic therapies and combinations Immune enhancing therapies Cytotoxic response in malignant cells

29 Skin-directed Therapies Topical corticosteroids Topical chemotherapy Nitrogen mustard (Mustargen) Carmustine (BCNU) Topical retinoids/rexinoids Bexarotene (Targretin) Tazarotene Phototherapy NB-UVB PUVA Radiation Electron beam radiation Site-directed radiation

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31 Targeted therapies Immune checkpoint blockade MicroRNA inhibitors

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33 30 (32) pts eligible ORR: 21 (70%) of 30 Highly variable CD30 expression Lower response with < 5% CD30 expression (P.005) CD163 positive tumor-associated macrophages express CD30 Most common AE: peripheral sensorial neuropathy

34 Sézary Syndrome

35 Anti-CCR4 Monoclonal Antibody, Mogamulizumab, Demonstrates Significant Improvement in PFS Compared to Vorinostat in Patients with Previously Treated Cutaneous T-Cell Lymphoma: Results from the Phase 3 MAVORIC Study Youn H. Kim, MD 1 ; Martine Bagot, MD 2 ; Lauren Pinter-Brown, MD 3 ; Alain H. Rook, MD 4 ; Pierluigi Porcu, MD 5 ; Steven Horwitz, MD 6 ; Sean Whittaker, MD 7 ; Yoshiki Tokura, MD, PhD 8 ; Maarten Vermeer, MD 9 ; Pier Luigi Zinzani, MD 10 ; Lubomir Sokol, MD, PhD 11 ; Stephen Morris, MD 7 ; Ellen J. Kim, MD 4 ; Pablo L. Ortiz-Romero, MD 12 ; Herbert Eradat, MD 13 ; Julia Scarisbrick, MBChB, FRCP, MD 14 ; Athanasios Tsianakas, MD 15 ; Craig Elmets, MD 16 ; Stephane Dalle, MD, PhD 17 ; David Fisher, MD, PhD 18 ; Ahmad Halwani, MD 19 ; Brian Poligone, MD, PhD 20 ; John Greer, MD 21 ; Maria Teresa Fierro, MD 22 ; Amit Khot, MD 23 ; Alison J. Moskowitz, MD 6 ; Karen Dwyer 24 ; Junji Moriya 24 ; Jeffrey Humphrey, MD 24 ; Stacie Hudgens 25 ; Dmitri O. Grebennik 24 ; Kensei Tobinai, MD, PhD 26 ; Madeleine Duvic, MD 27 for the MAVORIC Investigators Kim YH et al. Lancet Oncol 2018

36 Response outcomes Mogamulizumab Vorinostat ORR a,b, n/n (%) 52/186 (28) 9/186 (5) MF c 22/105 (21) 7/99 (7) SS b 30/81 (37) 2/87 (2) Stage IB/IIA 7/36 (19) 5/49 (10) Stage IIB 5/32 (16) 1/23 (4) Stage III 5/22 (23) 0/16 (0) Stage IV 35/96 (36) 3/98 (3) DOR, median, months 14 9 MF 13 (n=22) 9 (n=7) SS 17 (n=30) 7 (n=2) ORR a n/n (%) mogamulizumab after crossover 41/136 (30) a ORR is the percentage of patients with confirmed CR or confirmed PR; b P<0.0001; c P=0.004.

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38 CTCL cells The CC chemokine receptor 4 (CCR4) is expressed on malignant T cells in cutaneous T-cell lymphoma (CTCL) as well as on regulatory T cells Tregs Ni X et al. Clin Cancer Res 2015

39 Targeted therapies Immune checkpoint blockade MicroRNA inhibitors

40 CTCL Microenvironment Heterogeneity Multispectral Imaging CD4 PD1 PD-L1 CD8 DAPI

41 Cancer Immunotherapy Trials Network Protocol # CITN-10 A Phase 2 Study of Pembrolizumab for the Treatment of Relapsed/Refractory Mycosis Fungoides and Sézary Syndrome Principal Investigator: Y Kim, H Kohrt (Co-PI) Lead Sub-I: M Khodadoust Z Rahbar, J Kim (pathology), S Li (biostatistician) Stanford University SOM Investigative sites/site PI: A Rook (U Penn), F Foss (Yale), PG Porcu (OSU), A Shustov (SCCA), A Moskowitz (MSKCC), L Sokol (Moffitt), S Shanbhag (Johns Hopkins)

42 Pembrolizumab for Treatment of Relapsed/Refractory Mycosis Fungoides and Sézary Syndrome: Clinical Efficacy in a CITN Multicenter Phase 2 Study 24 patients Median age was 67 (range 44-85); 18 were male 23 patients (96%) with advanced MF - stage IIB or higher 15 patients (63%) with stage IVA SS Median follow-up time was 40 weeks (range 9-60 weeks) ORR was 38%, 1 CR and 8 PR There was no significant association between response and clinical characteristics including stage, disease type (MF vs. SS), and number of prior therapies, nor with skin tissue expression of PD-1, PD-L1, PD-L2, or infiltrating CD8+ T- cells as determined by IHC Khodadoust M et al; Blood :181

43 PD-L1 is Expressed on Antigen Presenting Cells A. B. C. Querfeld C et al. Blood a:821, 2017

44 Preliminary Results from Phase I Trial of Durvalumab and Lenalidomide 60 Durvalumab+Lenalidomide Change of Skin Score (%) pt. 4 pt. 6 pt. 9 pt. 5 pt. 8 pt. 1 pt. 7 pt. 3 pt CTCL Patients Querfeld: LLS Clinical Scholar NCI R01

45 Anti-PD-L1 (durvalumab) + lenalidomide Baseline Cycle 3 Day 15

46 CD47 - SIRPα Innate Immune Checkpoint Blockade for Halting Cancer Progression Result: No phagocytosis Tumor cells protected from immune response Progression of cancer Result: Phagocytosis of tumor cells Tumor cells are not protected from immune response Impaired progression of cancer Weiskopf K. Eur J Cancer 2017 CD47 binds to signal-regulatory protein (SIRPα) - an inhibitory receptor expressed on phagocytic cells

47 10 mg single injection of TTI-621 (Querfeld, City of Hope) Baseline: April5 Started PI3K inhib: May 17 Patient injected April 5 April 8: mild improvement to the injected plaque May 17: marked improvement of ulcerated plaques/tumors on foot and stable disease on trunk and extremities Long term follow up: July 10

48 Left lateral lower leg Baseline Day Day 8

49 Autoimmune Reactions: Pneumonitis Colitis Blistering disorders Endocrine abnormalities (autoimmune thyroiditis) Fibromyalgia

50 Targeted therapies Immune checkpoint blockade MicroRNA inhibitors

51 First-In-Human Phase 1 Study of MRG-106 in Patients with Mycosis Fungoides MRG-106 is an optimized oligonucleotide inhibitor of mir-155 formulated in saline Study objectives: Primary objective: Safety and tolerability Secondary objectives: PK profile, efficacy, recommended Phase 2 dose and route of administration Study Design: Subjects permitted to continue CTCL therapy if stable dose > 4 weeks prior to MRG-106 administration Part A: Activity of MRG-106 through intralesional injection Part B: Dose-escalation by systemic administration (subcutaneous or I.V.) Dose schedule for systemic administration: Three doses in the first week followed by weekly doses 51

52 122 transcripts A. C. Up-regulated vs. untreated Down-regulated vs. untreated Saline MRG-106 B. MRG-106 (µg/g tissue) BLOQ BLOQ Saline MRG-106 Figure 3: A) Log2 fold-change in gene expression for drug or saline treatment vs. pretreatment for each individual biopsy. Shown are 122 genes regulated in the same direc by MRG-106 in all 4 lesions. Red = increased expression relative to the median for all samples; blue = decreased expression relative to the median for all samples. B) MRG-106 tissue concentration detected by mass spectrometry in each biopsy. BLOQ = below the level of quantitation for the assay C) Annotation of genes up-or downin CD4+ T cells after treatment with PBS or cobomarsen.

53 Baseline Patient Characteristics: Part A n = 6 Part B n = 30 Total n = 36 Demographic Sex Male (n, %) 5 (83%) 20 (67%) 25 (69%) Age Median years (Min, Max) 61 (50,64) 63 (21,85) 63 (21,85) Race Asian 0 (0%) 1 (3%) 1 (3%) Black 1 (17%) 3 (10%) 4 (11%) Not reported 1 (17%) 0 (0%) 1 (3%) Other 0 (0%) 2 (7%) 2 (6%) White/Caucasian 4 (67%) 24 (80%) 28 (78%) Disease Stage at Screening Stage IA 0 (0%) 6 (20%) 6 (17%) Stage IB 1 (17%) 8 (27%) 9 (25%) Stage IIA 2 (33%) 3 (10%) 5 (14%) Stage IIB 3 (50%) 9 (30%) 12 (33%) Stage IIIA 0 (0%) 1 (3%) 1 (3%) Stage IIIB 0 (0%) 3 (10%) 3 (8%) Prior Systemic Therapies No of pts. reporting Median (range) 4 (1,6) 3 (1,13) 4 (1,13) Baseline mswat per Subject m ir-155 Copy Num ber in M F Lesion Biopsies m ir-155 copy num ber/10 pg RNA LLOQ norm al baseline skin lesion biopsies N=10 N=20 N

54 Case Example ( ): 300 mg IV Infusion Cohort Age: 51; Sex: Male Date of diagnosis: 2013 CTCL stage at screening: IB Baseline mswat: 180 Concomitant systemic therapy: weekly Methotrexate (started June 2015) Has skin (mswat) PR lasting > 4 months Day 1 mswat: 180 Day 93 mswat: 68 (62% reduction) 54

55 Care and Quality of Life Monitor for cutaneous infections Bacterial (S. aureus) Viral (HSV, VZV, HHV6) Monitor for other skin cancers Pruritus, pain Nutritional deficiencies Psychological needs

56 Quality of Life Assessment in CTCL Patients

57 Conclusions Cutaneous T cell lymphoma is a devastating and incurable disease. The microenvironment plays a profound role in its progression. Immunotherapy holds great promise in the treatment of cutaneous T cell lymphomas. Clinicopathologic correlation and healthy dialogue among a multidisciplinary team is critical

58 City of Hope Steven Rosen Larry Kwak Dennis Weisenburger Steven Forman Xiwei Wu Tijana Talisman Sung Hee Kil Renee Estephan Patrick Young Joycelynne Palmer Lu Chen James Sanchez Peter Lee & Lab Jasmine Zain Farah Abdulla Erin Kopp Karen Huelsman Estella Barrios Xochiquetzal Martinez Linda Lee Lilit Stepanian Thank You Supported by: Toni Stephenson Lymphoma Center Thank you to all our patients