Case Presentation

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Case Presentation

• 69 y/o woman presented 2001 with erythroderma,
  severe pruritis
• Dx Sezary Syndrome (PB, skin bx neg)
• PUVA 10/01-3/03 CR and then developed adenopathy
• 3/03 LNBx involvement T-cell lymphoma
  pathologic features are c/w, albeit not specific
  for MF/SS
• 3/03 Ontak 1 cycle - responded but developed
  severe maculopapular rash secondary to drug (seen
  in 20 of pts)
• 5/03-1/04 Targretin PR and then PD
• 2/04-1/05 Photopheresis, prednisone - SD

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Case Presentation

• 1/05 marked PD, nodes ?, WBC 45k, LDH gt1000
• 1/05- 5/05 Cytoxan, prednisone PR
• 6/05 - PD
• 7/05 Skin bx panniculitic T-cell lymphoma
• 8/05 MEDI-507 (anti-CD2 MAb) 1 cycle
• 9/05 Rapid Progression, WBC - 130k, LDH 1100
• Doxil, Gemcitabine

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Current Therapies for Advanced Stage Mycosis
Fungoides
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Prognosis of MF/SS
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Therapy Overview - MF/SS

• Goals improve symptoms, cosmesis, relapse-free
  survival

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Chemotherapy for MF/SS

• High response rates (40-80)
• Short response duration (6-12 mo)
• Methotrexate
• Alkylators
• Anthracyclines
• Purine analogs
• Gemcitabine
• Histone Deacetylase Inhibitors

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Liposomal Doxorubicin for MF/SS

• Liposomal preparations
• Longer circulating half-life
• Greater uptake in tumor vs. normal tissue
• Limited myelosuppression, less cardiotoxic
• Retrospective study (Wollina U, Cancer 2003)
• 34 pts with MF/SS (8 prior chemo)
• 20-40 mg/m2 Q14-28 d
• RR 88
• Median remission duration 13 mo

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Purine analogs for MF/SS
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Gemcitabine for MF/SS

• Cytarabine analog
• Phase II study (Zinzani PL, JCO 2000)
• 30 pts
• Median of 3 prior treatments (2-5)
• 1200 mg/m2 D1, 8, 15 Q28d
• RR 70
• Median remission duration 10 (PR)-15 mo (CR)
• No grade 3,4 toxicities

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Histone Deactylase Inhibitors for MF/SS

• Depsipeptide and SAHA (suberanilohydroxamic acid)
• Phase I study of depsipeptide - 2/2 CTCL and 1/1
  PTCL (Piekarz Blood 2001)
• Phase II study of depsipeptide ongoing (Piekarz,
  ASH, 2003)
• RR 57 in 14 pts with 2 prior chemo regimens
• Arrhythmias
• SAHA (oral) Phase II study for CTCL ongoing

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ONTAK (Denileukin Diftitox) for MF/SS(Olsen E et
al. JCO 19376, 2001)

• Fusion protein IL-2 diphtheria toxin
• Binds to IL-2R and internalized
• Acidification ? active DT into cytosol
• Pivotal Phase III trial of 2 dose levels
• 9-18 mcg/kg d1-5 Q21d
• RR 30, med remission duration 7 mo
• Overall no difference 2 dose levels RR, duration
• Stage IIb-IV RR 9 mcg (2/21 9), 18 mcg (9/24
  38)
• Capillary leak syndrome decreased incidence
  with steroid premedication

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Bexarotene (Targretin) for MF/SS

• Retinoid X receptor (RXR) selective retinoid
• Phase II study in stage IIb-IV
• Refractory to at least one prior systemic therapy
• 300 mg/m2/day
• RR 45 (equal in all stages)
• Median remission duration 10 mo
• Hyperlipidemia, central hypothyroidism common

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Bexarotene ONTAK(Foss et al., Blood 106 454
2005)

• Bexarotene upregulates IL-2R in vitro
• Enhanced susceptibility of leukemic cells 5-10
  fold to ONTAK
• Phase I trial Bexarotene ONTAK
• Bexarotene daily starting D -8 cycle 1
• Dose escalation 75 mg, 150 mg, 225 mg, 300 mg,
  375 mg
• 14 pts
• No DLT, similar toxicities as single agents
• RR 67
• IL2R modulated at doses 150 mg

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Monoclonal Antibodies for MF/SS

• CAMPATH anti-CD52
• MEDI-507 anti-CD2
• HuMAX-CD4 anti-CD4

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Alemtuzumab (CAMPATH) for MF/SS(Lundin J, Blood
1014267, 2003)

• Humanized Anti-CD52 MAb (pan-B, T-cell antigen)
• Highly immunosuppressive, serious infections
  common, ? cardiac toxicity in MF
• Phase II study
• 30 mg 3x/wk
• RR 55 (32 CR) in 22 pts (69 T4, 40 T3)
• Median TTP 12 mo
• CMV reactivation 18, fatal aspergillosis (1),
  fatal TB (1)
• Studies with subQ administration underway-less
  toxic

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Anti-CD2 for MF/SS

• Humanized MAb binds to CD2 receptor on T-cells
• Activity in animal model of CD2 lymphomas
• Ongoing trials for GvHD, psoriasis
• Two Phase I studies of MEDI-507 in T-cell
  lymphomas
• NCI 3/9 PRs
• Multicenter (Wash U) no data, IV d1-3 Q14d
• Concern re CMV reactivation, opportunistic inf.

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Anti-CD4 for MF/SS

• Chimeric anti-CD4 (Blood. 87(3)893-9, 1996)
• Single dose
• RR in Phase I 7/8 responders, no infections
• Phase II complete
• Humanized MAb (HuMax-CD2)
• Mechanism of action thought to be thru ADCC
• Multicenter Phase I/II for MF ongoing (Wash U)
• IV weekly x 12 weeks

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Allogeneic Stem Cell Transplant for MF/SS
(Molina et al J Clin Oncol 236163 2005)

• Retrospective series from City of Hope
• 8 pts. advanced MF/SS underwent allo -SCT
  between 8/96 10/02
• Failed median 7 prior treatments (range 5 12)
• Conditioning
• TBI/Cy 3
• BuCy 1
• Reduced Intensity Conditioning (RIC) 4
• HLA matched sib 4, MUD 4
• BM 3, PBSC 5

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Patient Characteristics
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