Nuevos tratamientos LCCT - seap.esDr.+Ortiz+Nuevos... · Recommendations category 2A “lower level...

Dr. Pablo L Ortiz Romero Servicio de Dermatología Hospital 12 de Octubre

Nuevos tratamientos LCCT

Mycosis fungoides

Sézary Syndrome

MF and SS, 66% of CTCL Therapeutic options Choice of treatment

Institutional experience Doctor’s preferences Patient’s decission

We do not have standard treatment for MF/SS

Several guidelines have been published

Several guidelines have been published

Recommendations category 2A “lower level evidence, including experience”

No class 1 level

Several guidelines have been published

Treatment considerations SS, agressive but MF, indolent

Before treating MF/SS we need to understand it

Survival MF/SS

Treatment considerations SS, aggressive but MF, indolent No curative treatment. No treatment has shown increase of survival Objective: Increase QoL

Achieve CR Increase DFS Minimal toxicity during treatment Minimal long term problems

Before treating MF/SS we need to understand it

Prince et al. Blood 2009

El pronóstico de MF/SS depende del estadio

Skin Directed therapy Emollients Topical corticosteroids Nitrogen mustard BCNU (carmustine) Topical bexarotene PUVA UVB/nbUVB/láser Photodynamic therapy TSEB Superficial X irradiation… …

Systemic therapy IFN alpha Retinoids Bexarotene Extracorp. photopheresis Denileukin difitox Alemtuzumab Monochemotherapy Polychemotherapy HuMaxCD4 Vorinostat Depsipeptide LBH589… …

We have plenty of different MF/SS treatments

No tenemos tratamiento estándar para MF/SS

Nivel de evidencia bajo Escasez de ensayos clínicos

randomizados

Tratamiento LCCT

Ontak vs placebo Placebo arm: 44 patients ORR PFS Early, n:30 1CR, 2PR 107d Advanced, n:14 4 PR 211d

Placebo can improve advanced MF.

Prince et al, JAAD, 2011 HM Prince, JCO, 2010

New treatments Chemotherapeutic agents Monoclonal antibodies Epigenetic treatments Immune stimulation approach Old treatments with new approach

New treatments for MF/SS

Chemotherapy

Kaye FJ et al. NEJM, 1989;321:1784-90

Mono/polichemo MF/SS, chemoresistant Low proliferative rate MF Ia, Ib, IIa, not recommended Polichemo >CR rate, >>> toxicity than SDT No differences with PFS nor OS with SDT

Chemotherapy.

Pralatrexate (Folotyn ®) Antifolate. FDA approved Sept 09 (PTCL) Selectively enters cells RFC1+ + VitB12 + Folic acid. ORR: MF-t: (30mg/m2) 25% RR (2CRs) MF (15mg/m2, ¾ sem): 28%RR Toxicity: Mucositis, nausea, fatigue Gr3-4: Fatigue, cut. toxicity, thrombopenia. ADD LEUCOVORIN!!!

F Foss et al. Clin Lymph Myel Leuk, 2012 SM Horwitz et al.Blood 2012 E koch. Leukemia lymphoma 2013

Courtesy Dr L Geskins

Chemotherapy.

Pegilated liposomial doxorubicin (Caelix ®)

Phase II, EORTC 21012 49 patients (IIb-IVb) RR: 40% 3CR, 17PRs Median TTP: 7.4 m Median DOR: 6m Toxicity: PPE

Cardiomyopathy

Woolina U et al, Cancer, 2003 R Dummer et al. In press.

Chemotherapy.

Purine nucleoside analogues Purine Nucleoside Phosphorilase (PNP)

selectively expressed by T-cells Deficiency produces low T-cell, normal B-cell

Forodesine Nelarabine: No efficacy. High toxicity Clofarabine

Larson PA. Semin Oncol 2007

Chemotherapy.

Forodesine (Bcx1777) Purine Nucleoside Phosphorylase (PNP inhibitor) T-cell selective apoptosis Phase I/II: 64 cases (80% IIb or higher) All cases ORR 39% (3CR, 14 PR) Erythrodermic ORR 65% (2CR, 11PR) Median TTR: 42d Median duration of response: 127d+ Toxicity: Nausea, fatigue, peripheral edema, pruritus Grade 3 AE: Pneumonia, cellulitis, diarrea Phase II completed

Y Kim et al. EORTC CLTF meeting. Copenhaguen 2008

MF: Systemic treatments.

Y Kim et al. EORTC CLTF meeting. Copenhaguen 2008

MF: Systemic treatments.

New treatments Chemotherapeutic agents Monoclonal antibodies Epigenetic treatments Immune stimulation approach Old treatments with new approach

New treatments for MF/SS

CD52

CD2

CD3 CD4 CD25

Alemtuzumab (Campath ®)

30 mg, i.v. 3 d/w RR: 55% CR: 32% (22 patients) > efficacy erytrodermy (RR 69%) Time to progression: 12m Toxicity: Inmunosupression

Lundin J et al, Blood, 2003 Bernengo et al. Haematologica 2007

Monoclonal antibodies

CD52

CD2

CD3 CD4 CD25

Alemtuzumab (Campath ®)

Low dose subcutaneous Alemtuzumab 14 SS patients (11 refractory) 3 mg 1st day 4 patients: 15 mg eod 10 patients: 10 mg/eod, (14 pts, 3CR, 9PR) No infections No toxicity (in the low dose)

Bernengo et al. Haematologica 2007

Monoclonal antibodies

CD52

CD2

CD3 CD4 CD25

38 MF, 9 SS (Ib-IVb) MF (280 mg/w): RR 15% (560-980 mg/w): RR 56% (2CR,10PR) SS: RR 22% (2PR) Median time to response <8w Median response duration 81w Toxicity: Hipersensitivity, infections, GOT/GPT, pruritus, muscle fibre break, febrile T-penia, neutropenia Prolongued CD4 reduction (even >24 mo)

Obitz E et al, Blood, 2003 Y Kim et al. Blood, 2007

HuMax-CD4 (Zanolimumab)

Novel therapies for MF/SS

CD52

CD2

CD3 CD3 CD25

Diphteria toxin fused to 2 single chain Fv fragments of antiCD3 epsilon moAb Phase I 2.5-5 µgr/k/12h x 4 d 8 patients evaluable: (1-8 prev. treatm) 2 CR, 3PR Both CR, stage Ib Toxicity Fever, nausea, chills Lymphopenia (recovers in 2w) Reactivacion vEB (5) and CMV (3)

Frankel AE et al. Curr Drug Targets 2009

CD3 immunotoxin

New treatments for MF/SS

CD30

CD2

CD3 CD4 CD25

SGN30 AntiCD30 moAB Interferes G1. Apoptosis Phase II, 23 patients (3PL, 3TumMF, 11pcALCL) 6 patients multiple 4 12 mg/k/3 sem x6 doses RR: 70% (10CR, 6 PR) MF: PR 1/3 cases Toxicity: Fatigue, Diarrea, pruritus

M Duvic et al. Clin Cancer Res 2009

Novel therapies for MF/SS

CD30

CD2

CD3 CD4 CD25

SGN35 Brentuximab Bedotin Adcetris ®

SGN30 + MM Auristatin E Aprobado FDA para LH y sALCL 1.8 mg/k, iv /21d x 16 cycles Same mechanism as SGN30 Anti tubulin effect. Blocks G2-M Investigator initiated clinical trial Responses even in CD30- patients Phase II ongoing for MF/Ki1 24 MF patients. (31% RR) 1 CR

M Duvic et al. ASH 2012

New treatments for MF/SS

RECLUTAMIENTO EN EL 12 DE OCTUBRE y VALLE HEBRÓN

Se necesitan pacientes

CD52

CD2

CD3

CCR4

CD25

Expressed mostly Th2 cells Expression MF>>normal T cells Defucosilated humanized anti CCR4 Phase 1-2. 1 mg/k iv/w x 4 w + observ.2w Median 5 previous treatments 17 SS (1 CR, 7 PR) (ORR47%) 21 MF (1CR, 6 PR) (ORR 29%) Blood involvement responds better Adverse events (>15%) Nausea, headache, chills, pyrexia drug eruption, diarrhea NO INFECTIONS. Pivotal RCT ongoing.

M Duvic et al ASH 2010

CCR4. AMG761 Mogamulizumab

New treatments for MF/SS

RECLUTAMIENTO EN EL 12 DE OCTUBRE Y SALAMANCA

Se necesitan pacientes

New treatments Chemotherapeutic agents Monoclonal antibodies Epigenetic treatments Immune stimulation approach Old treatments with new approach

New treatments for MF/SS

HDACi

Novel therapies for MF/SS

Vorinostat

HDAC I, II y IV

+

Transcription Factor Acetylation

G1

S

G2 M

CD40

MHC

MICA

Cell Cycle Angiogenesis Apoptosis Immune Modulation

Differentiation

+

Non-transcriptional Effects Mitotic Catastrophe Hsp90 Inactivation

Ac Ac Ac Ac Ac Ac

Ac

Ac Ac Ac Ac Ac Ac Ac

Ac Ac

Hsp90

+

Transcriptional Effects Histone Acetylation

Ac Ac Ac Ac Ac Ac

Ac Ac Ac Ac Ac Ac

Ac Ac Ac

Novel therapies for MF/SS

HDACs inhibitors Vorinostat (SAHA)

Phase II: 37 patients 27 % RP (no RC)

Phase IIb: 74 patients RR: 29.5%

>80% stage ≥IIb Median time to response: 8-12 w. Median time to progression: 4.9 mo (9.8mo if >IIb) Toxicity: Diarrhea, fatigue, nausea ( >40%…)

Thrombocytopenia M Duvic et al. ASCO 2005 E Olsen et al. J Clin Oncol 2007. Approved FDA 9 Oct 2006

Novel therapies for MF/SS

HDACs inhibitors Vorinostat

Courtesy L Geskins E Olsen et al. JCO, 2007

Baseline (May 2005) Week 17 Response (Initial)

51% in SWAT Score Week 38 Response

70% in SWAT Score

Novel therapies for MF/SS

Tto prolongado. M Duvic et al. Clin lymphoma myeloma 2009

6 patients >2y Most frequent toxicity Diarrea (100%) Fatigue (67%) Nausea / Alopecia: 50%

Grade 3-4 toxicity Thrombopenia Pulmonary embolism Anorexia Evoluction: 2 patients progress

Novel therapies for MF/SS

HDACs inhibitors Depsipeptide (Romidepsin) Pooled analysis 2 CT (71+96 pat.)

167 patients MF, Ib-IVa (135 evaluable) 76% ≥IIb ORR: 41% (55 patients) 10 CR 45 PR SS: 11/19 (58% responses) Median time to resp: 8w

Toxicity: Nausea, fatigue vomiting, Tpen, Npen SAE: 2% (SupraV and V arrythmia Infections

Piekarz R et al. ASCO 2009 Approved FDA Sept 2009

Novel therapies for MF/SS

Week 4 Week 2 Week 3

1 22 15 8 1

Week 1 Cycle 1

Week 1 Cycle 2

Adopted schedule: 4-hour infusion 14 mg/m2 on days 1, 8, & 15 every 28 days

Romidepsin Romidepsin Romidepsin Romidepsin

Marshall JL et al. Exp Ther Oncol. 2002;2:325-332 Courtesy L Geskin

HDACs inhibitors Depsipeptide

Novel therapies for MF/SS

LBH589 (Panobinostat®): Phase I: 11 patients (2CR, 4PR,

20mg p.o. 3d/w 2 late responses, 2 mo after withdraw) Median to progression: 7m.

HM Prince et al. ASCO 2006

HDACs inhibitors

Novel therapies for MF/SS

LBH589: Phase I: 11 patients (2CR, 4PR,

2 late responses, 2 mo after withdraw) Median to progression: 7m.

HM Prince et al. ASCO 2006

HDACs inhibitors

Patients who have received at least 2 prior systemic treatment regimens

No prior treatment with a DAC inhibitor

Prior oral bexarotene Oral bexarotene naïve

Stage 2 (26 patients)

Stage 2 (26 patients)

Stage 1 (33 patients)a

Stage 1 (33 patients)

Continue to Stage 2 if 3 responders

Reject inactivity if 7 responders

HDACs inhibitors

M Duvic et al. Eur J Cancer 2013

Panobinostat. Phase II

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Patients (N=66) Patients (N=35)

2CR, 9 PR (ORR 15%) 4CR, 6 PR (ORR 20%)

Panobinostat. Phase II HDACs inhibitors

M Duvic et al. Eur J Cancer 2013

HDACs inhibitors

M Duvic et al. Eur J Cancer 2013

Panobinostat. Phase II

HDACs inhibitors

PXD 101 (belinostat): Fase II. NCI. Activo 22 pts, MF Ib-IVb. 1 RC, 3 RP Time to response: 15 days Duration of response: +13w Adverse events: Nausea, fatigue, vomiting, pruritus

Pohlman B et al. Pan Pacific Lymphoma Conf, 2007 R Alvani et al. ASH meeting, 2007 Y Kim et al. EORTC CLTF meeting, Copenhagen

Novel therapies for MF/SS

LBH589 (Panobinostat®)

HDACs inhibitors

Epigenetic treatments

PXD 101 (Belinostat)

Quisinostat

Bortezomib (Velcade ®)

Inhibits proteasome 26S Degrades p21, p27, p53, NFKB, IKB… Blocks post aggression survival ways Reduces chemo resistance Phase II 12 evaluable patients (10 MF, 2 PTCLU)

RR: 67% (2CR, 6PR, 4 progress) Toxicity (Gr 3): Neutropenia, T pen, neuropathy Ongoing phase II, NCI

Zinzani et al. J Clin Oncol, 2007

Proteasome inhibitors

New treatments Chemotherapeutic agents Monoclonal antibodies Epigenetic treatments Immune stimulation approach Old treatments with new approach

New treatments for MF/SS

NUEVOS TRATAMIENTOS DE MICOSIS FUNGOIDE

Estímulo respuesta inmune innata

Toll-like receptors

Reconocen patrones

Diferencian propio vs. extraño

NUEVOS TRATAMIENTOS DE MICOSIS FUNGOIDE

Toll-like receptors Activan NFKB Estimulan maduración

célula present. Ag Liberan citoquinas

proinflamatorias Estimulan células NK

y CD8

Estímulo respuesta inmune innata

Imidazoquinoleines Imiquimod Stimulates TLR 7 and 8 3 times/w, 12 weeks (6 cases) RR: 50% (MF patch/plaque stage) Time to response: 4w.

Deeths MJ et al. JAAD 2005 Martinez MC EJD, 2008

Skin directed strategies.

Oligodeoxynucleotide CpG CpG 7909 (Promune ®)

Stimulate TLR 9 Phase I (Y Kim et al, ASCO 2005) 12 patients MF, 1 CR, 3 PR

Kim Y et al. Blood 2005 Kim Y et al. ASH 2010

Skin directed strategies.

NUEVOS TRATAMIENTOS DE MICOSIS FUNGOIDE

Oligos CpG + RT CpG 7909 (Promune ®)

Kim Y et al. Blood 2012

15 patients 5 “clinically meaningful responses”

enzylguanine

NUEVOS TRATAMIENTOS DE MICOSIS FUNGOIDE

Oligos CpG + RT CpG 7909 (Promune ®)

Kim Y et al. Blood 2012

New treatments Chemotherapeutic agents Monoclonal antibodies Epigenetic treatments Immune stimulation approach Old treatments with new approach

New treatments for MF/SS

NUEVOS TRATAMIENTOS DE MICOSIS FUNGOIDE

IFN γ en vectores adenovirales TG-1042 9 pacientes

RR: 5/9 (3RC, 2RP) 3 pacientes con efecto a dist.

R Dummer et al, Blood 2004 Adenovirus humano no replicante

Fase II en curso Datos de 31 pac: 17/31: respuesta local (9 RC, 8 RP)

M Urosevic et al. ASCO 2006

NUEVOS TRATAMIENTOS DE MICOSIS FUNGOIDE

R Dummer et al, Blood 2004

IFN γ en vectores adenovirales

Radiotherapy MF very radiosensitive. Low doses Retreatments, possible Thick plaques / tumors Electrons / superficial X irradiations Localised RT

Unilesional MF: 100% CR, 86% RFS at 10y Tumoral lesions: 90% treated lesions, CR

Micaili B et al. Int J Radiat Oncol Biol Phys 1998;42:361-4

Skin directed strategies.

Total Skin Electron Beam Systematic review 952 cases Series. Retrospectives. Open, not controled Responses, stage-dependent

CR 36% IIb CR 60% III.

Respuestas dose and energy dependent Maximum 3 retreatments

Cotter GW et al. J Radiat Oncol Biol Phys 1983;9:1477-50 Jones GW, et al:. Haematol Oncol Clin North Am 1995;9: 1057–76. Jones GW et al . Cancer 1999; 85: 1985–95. Hamminga B et al: Arch Dermatol 1982; 118: 150–3.

Skin directed strategies.

Helical tomotherapy Photons Helical machine (similar helical CT scan) Max 160 cm. Difficulties dosification Risk deep irradiation.

N Hardcastle et al. Med Phys 2008

Old treatment. New approach.

Búsqueda de nuevas dianas

PLCG1, mutada

Tacrolimus

RC 1 mes con tacrolimus 0.1% Rebrota 2 m. después. Responde de nuevo

MF folliculotropa. Unilesional RP tras 4m.

Rallis E. J Drugs Dermatol 2006

Ally MS et al. JAAD 2012

Hay casos en la literatura tratados con tacrolimus

12 pacientes 1 RC, 5 RP, 2 EP

Pre tratamiento Tratamiento 30 dias

Un paciente consiguió RC

5 pacientes, respuesta parcial

+60d

5 pacientes, respuesta parcial

Tacrolimus +120d

Clobetasol

60 días

5 pacientes, respuesta parcial

30 días Pre tto

2 pacientes, progresión

ARO

Pre tratamiento Tratamiento (3 días)

ARO

Pre tratamiento 40 días

ARO

Pre tratamiento 120 días

GRACIAS