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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
% C
hang
e in
mSW
AT s
core
to
min
imum
pos
t-bas
elin
e va
lue
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