Cutaneous TCell Lymphoma

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Cutaneous T-Cell Lymphoma

• Shachar Peles M.D.
• Hematology Oncology Grand Rounds
• September 26, 2003

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Case Presentation

• 52 year old
• Left forearm rash for 4 years
• Intermittent erythematous patches
• Left forearm rash flared up nodular, rapidly
  progressing

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Case Presentation

• PMH Polio age 4
• Cyst removal near parotid 30 yrs ago
• Meds Centrum Silver, Gingko
• All NKDA
• SH 1ppd x 25 years. Social Etoh.
• FH F died age 92 CHF
• M Alzheimers
• S x 2 Alive and Well

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Case Presentation

• PE 192lb 68in HR76/min BP 130/74
• Derm Left forearm 3 x 2.5cm nodules with
  surrounding erythroderma
• HEENT Anicteric, conj pink, OP clear
• Neck Supple, No LAD
• Lungs CTAB
• CVS RRR No M/R/G
• Abd ND, SNT, No HSM, BS
• Ext No edema
• Lymph no axillary,cervical,supraclav,inguinal LAD

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Case Presentation

• Lab Data
• Hgb 15.3 Plt 145
• WBC 7200, normal differential
• Skin Biopsy
• Mycosis Fungoides

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Primary Cutaneous T-cell Lymphoma

• Lymphoproliferative disorders
• Neoplastic T lymphocytes localized in the skin at
  presentation
• Several distinct disorders
• Mycosis Fungoides and Sezary Syndrome most common

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Revised European-American Lymphoid Classification

• T-Cell Lineage
• Indolent Lymphomas
• Large Granular Lymphocytic Leukemia, T NK cell
  types
• Mycosis Fungoides/Sezary syndrome
• Smoldering and Chronic adult T-cell
  leukemia/lymphoma (HTLV-I)
• Aggressive Lymphomas
• Prolymphocytic Leukemia
• Peripheral T-cell Lymphoma
• Angioimmunoblastic Lymphoma
• Intestinal T-cell Lymphoma
• Anaplastic Large cell Lymphomas (T null cell
  type)
• Very Aggressive Lymphomas
• Precursor T-lymphoblastic Lymphoma/Leukemia
• Adult T-cell Lymphoma/Leukemia (HTLV-I)

Harris et al Blood 84 1361, 1994
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EORTC Classification for Primary Cutaneous
Lymphomas

• Indolent
• MF
• MF follicular mucinosis
• Pagetoid reticulosis
• Large-cell CTCL, CD30
• Anaplastic
• Immunoblastic
• Pleomorphic
• Lymphomatoid papulosis
• Aggressive
• SS
• Large-cell CTCL, CD30-
• Immunoblastic
• Pleomorphic
• Provisional
• Granulomatous slack skin
• CTCL, pleomorphic small/medium-sized
• Subcutaneous panniculitis-like T-cell lymphoma

Willemze et al Blood 90354-371, 1997
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CTCLs MF/SS - Epidemiology

• Uncommon, 0.29 cases MF per 100,000 population
  per year
• 2.2 of all lymphomas
• 3 fold increase in incidence of MF between 1973
  and 1984
• Incidence increases with age
• 2.2 times more common in men
• More common in African-Americans

Weinstock et al JAMA 26042-46, 1988
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CTCLs MF/SS - Etiology

• Remains unknown
• Chronic antigenic stimulation
• Chemicals
• Bacterial infections
• Viral Infections
• HTLV-I
• HHV-8
• Smoking
• Medications
• Chronic sun exposure
• Cytokines

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CTCLs MF/SS Clinical Presentation

• First case described in 1806 by Alibert mushroom
  like tumors
• 3 Phases of progression
• Macular erythematous eruption
• Plaque/Patch phase, resembles eczema/psoriasis
• Tumor nodules/erythroderma and associated
  adenopathy or visceral involvement
• Sezary Syndrome
• Generalized erythroderma pruritis
• Circulating malignant (Sezary) cells

Alibert Description des maladies de la peau
observees a lHopital St Louis, Paris, France
1806 Bazin Maladies de la peau Observees a
lHopital St Louis, Paris, France 1876 Koh et al
Hematol Oncol Clin North Am 9943-960, 1995
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CTCLs MF/SS Diagnosis

• Clinical Findings
• Skin Biopsy
• Immunophenotyping CD3, CD4, CD8-, CD30-,
  CD45RO, TCR gene rearrangements

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CTCLs MF/SS Staging TNMB

• T1 Limited patch/plaque (lt10 of skin surface)
• T2 Generalized patch/plaque (gt10 of skin
  surface)
• T3 Tumors
• T4 Generalized Erythroderma
• M0 No visceral metastases
• M1 Visceral Metastases
• B0 Atypical circulating cells not present (lt5)
• B1 Atypical circulating cells present (gt5)
• N0 No clinically abnormal peripheral lymph nodes
• N1 Clinically abnormal peripheral lymph nodes
• NP0 Biopsy performed, Not CTCL
• NP1 Biopsy performed, CTCL

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CTCLs MF/SS Staging

• IA T1 - Patch/Plaque
• IB T2 - Patch/Plaque
• IIA N1 - Clinical Nodes
• IIB T3 - Tumors
• III T4 - Erythroderma
• IVA NP1 - Path Nodes
• IVB M1 - Visceral Mets

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CTCLs MF/SS Prognosis

• Good-Risk
• Patch/Plaque only
• Survival gt12 years
• Intermediate-risk
• Tumors/erythroderma
• Plaque node/blood
• Survival 5 years
• Poor-risk
• Visceral involvement
• Survival 2.5 years

Sausville et al Ann Int Med 109372-382,
1988 Kim et al Arch Dermatol 1321309-1313, 1996
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CTCLs MF/SS Treatment

• Skin Directed
• PUVA
• Topical chemotherapy
• Radiation therapy
• Systemic
• Chemotherapy
• Photopheresis
• IFN
• Retinoids/Rexinoids
• Biologic Agents

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CTCLs MF/SS Treatment

• Cures generally unattainable
• Goals of treatment are symptom relief and
  cosmetic improvement
• Early aggressive therapy results in high complete
  remission rates but no significant difference in
  DFS or OS
• Kaye et al N eng J Med 3211784-1790, 1989
• Pts are susceptible to infections with skin
  flora immune suppression is undesirable
• Patch/Plaque Skin Directed Local/Total
• Refractory Plaque Systemic /- Skin Directed
• Erythroderma Systemic /- Skin Directed
• Tumor Lymph Rad Rx /- Systemic
• Node Rad Rx /- Systemic

22
CTCLs MF/SS PUVA

• Ingestion of 8-methoxypsoralen (0.6mg/kg, 2 hours
  before UVA exposure)
• Becomes activated when exposed to UV light
• Treatments 3x/wk with subsequent tapering
• 65 CR, 95 OR, duration of response 43 months,
  Mean survival 8.5 years in Stage I
• SE nausea, erythema, pruritis, dry skin,
  secondary skin malignancies

Herrmann et al J Am Acad Dermatol 33234-242,
1995
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CTCLs MF/SS Topical ChemoRx

• Nitrogen Mustard or BCNU
• Overall Response Rates 70-90 in Stage I disease
• SE contact dermatitis, secondary skin
  malignancies, erythema

Kim et al Arch Dermatol 139165-173, 2003
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CTCLs MF/SS Radiation Therapy

• CTCL is very radiosensitive
• Use of Electron Beam Therapy limits toxicity, lt5
  of dose travels beyond 2cm
• Standard total dose is 36 Gy
• CR 56-96 in Stage IA-IIA
• Given in combination with other agents to avoid
  relapse
• Toxicity erythema, pain, swelling, hair and nail
  loss, secondary skin cancer

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CTCLs MF/SS Photopheresis

• Reserved for Sezary Syndrome
• Pt ingests 8-MOP
• Leukapheresis, mononuclear fraction isolated and
  exposed to UVA, then returned to pt
• UVA is toxic to cells and reinfused cells
  stimulate a selective immune response against
  malignant cells
• RR 73, median survival 5 years in one study of
  pts with mainly SS
• Recent MD Anderson study RR 43 for monotherapy,
  56 in combination
• Catheter related sepsis

Edelson et al N Engl J Med 316297-303,1987 Talpu
r et al SID Abstract 1238
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CTCLs MF/SS Chemotherapy

• Single Agent MTX, Glucocorticoids, NM,
  Cyclophosphamide, Cisplatin, Etoposide,
  Bleomycin, Doxorubicin, Vincristine, Vinblastine
• Combination Alkylating agents
  Doxorubicin/Vinca alkaloids
• Purine Analogs (infectious complications)
• RR up to 100
• No significant survival benefits

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CTCLs MF/SS Interferon alpha

• ORR 79 in pts with all stage disease
• Maximum dose limited by side effects
• Started at 3million U and titrated up to maximum
  of 15million U 3x/wk
• In one study combining PUVA with IFN 12 million
  Units 3x/wk ORR 88, CR 62, response duration
  28 months

Kuzel et al J Clin Oncol 13257-263, 1995
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CTCLs MF/SS Bexarotene

• Novel Retinoid Rexinoid
• FDA approved for use in CTCL in patients who have
  not responded to at least one prior systemic
  therapy
• Selectively activates retinoid X receptors
  (nuclear hormone receptors)
• Acts on retinoid response elements to alter gene
  expression

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CTCLs MF/SS Bexarotene
Cheng, Kupper Arch Dermatol 137649-652, 2001
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CTCLs MF/SS Bexarotene
Cheng, Kupper Arch Dermatol 137649-652, 2001
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CTCLs MF/SS Bexarotene

• Approved by FDA following evaluation in 152 pts
  with advanced and early stage CTCL in 2 studies
• JCO 94 pt, stage IIB-IVB, OR 45, median
  duration of response 299 days

Duvic et al J Clin Oncol 192456-2471, 2001
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CTCLs MF/SS Bexarotene
Duvic et al J Clin Oncol 192456-2471, 2001
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CTCLs MF/SS Bexarotene Efficacy

• Stage responses
• IA 2/4 50
• IB 11/21 52
• IIA 2/3 67
• IIB 13/23 57
• III 6/19 32
• IV 6/14 43

Duvic et al J Clin Oncol 192456-2471, 2001
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CTCLs MF/SS Bexarotene Safety

• With 300 mg/m2/day
• Hypertriglyceridemia 63
• Most patients required lipitor and/or tricor.
  Diet should include Vitamin E and dietary
  consultation, especially for monotherapy
  patients.
• Hypothyroidism 43
• These patients needed synthroid supplements
• Leukopenia 7
• Dose adjustments controlled leukopenia

Duvic et al J Clin Oncol 192456-2471, 2001
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CTCLs MF/SS Systemic Therapy

• Bexarotene Interferon Photopheresis
• Dosing Oral Injection Hospital
  3-7d/week 4hx2dys/mth
• Availability Home Home or MD Office
  Select Hospitals
• Onset Dys-Wks Wks/Mths Wks/Mths
• Toxicity Lipids Depression/Flu-like Fluid
  shifts

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CTCLs MF/SS Skin Directed

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CTCLs MF/SS Bexarotene
F. J. Esteva, J. Glaspy, S. Baidas, L. Laufman,
L. Hutchins, M. Dickler, D. Tripathy, R. Cohen,
A. DeMichele, R. C. Yocum, C. K. Osborne, D. F.
Hayes, G. N. Hortobagyi, E. Winer, and G. D.
DemetriMulticenter Phase II Study of Oral
Bexarotene for Patients With Metastatic Breast
CancerJ. Clin. Oncol., March 15, 2003 21(6)
999 - 1006.
K. Wu, Y. Zhang, X.-C. Xu, J. Hill, J. Celestino,
H.-T. Kim, S. K. Mohsin, S. G. Hilsenbeck, W. W.
Lamph, R. Bissonette, and P. H. BrownThe
Retinoid X Receptor-Selective Retinoid, LGD1069,
Prevents the Development of Estrogen
Receptor-Negative Mammary Tumors in Transgenic
MiceCancer Res., November 15, 2002 62(22) 6376
- 6380.
Fadlo R. Khuri, James R. Rigas, Robert A. Figlin,
Richard J. Gralla, Dong M. Shin, Reginald Munden,
Nikolaus Fox, Mi Ra Huyghe, Yin Kean, Steven D.
Reich, and Waun K. Hong Multi-Institutional Phase
I/II Trial of Oral Bexarotene in Combination With
Cisplatin and Vinorelbine in Previously Untreated
Patients With Advanced NonSmall-Cell Lung Cancer
J. Clin. Oncol., May 15, 2001 10 2626-2637
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CTCLs MF/SS Denileukin Diftitox (Ontak)
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CTCLs MF/SS Denileukin Diftitox (Ontak)

• Recombinant fusion protein diphtheria toxin and
  IL2
• Gene is expressed in E. coli, resulting single
  polypeptide chain is able to inhibit protein
  synthesis in cells that express IL-2 receptor
  leading to cell death
• IL2 receptor complex CD25, CD122, CD132
• Ontak only internalized by cells with
  intermediate/high affinity receptor

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CTCLs MF/SS Denileukin Diftitox (Ontak)

• Response (tumor burden)
• Dose of DAB389 IL-2 CR CCR PR CR CCR PR
• No.
• 9 µg/kg/d (n 35)
• Ib 1 /7 2 /7 1 /7 4 /7 57
• IIa 2 /7 2 /7 29
• IIb 1 /9 1 /9 11
• III 0 /5 0
• IVa 1 /7 1 /7 14
• 18 µg/kg/d (n 36)
• Ib 1 /9 2 /9 3 /9 33
• IIa 1 /3 1 /3 33
• IIb 1 /10 1 /10 3 /10 5 /10 50
• III 2 /6 2 /6 33
• IVa 1 /8 1 /8 2 /8 25
• All (n 71) 3 /71 4 /71 14 /71 21 /71 30

Olsen et al J. Clin. Oncol. 19376-388, 2001
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CTCLs MF/SS Denileukin Diftitox (Ontak)

• 30 OR in heavily pretreated patients
• Symptomatic improvement
• Median response duration 6.9 months
• Toxicity
• Vascular leak syndrome
• Infusion reactions
• Constitutional symptoms
• Myelosuppression is uncommon

Olsen et al J. Clin. Oncol. 19376-388, 2001
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CTCLs MF/SS Denileukin Diftitox (Ontak)

• 30 OR in heavily pretreated patients
• Symptomatic improvement
• Median response duration 6.9 months
• Toxicity
• Vascular leak syndrome
• Infusion reactions
• Constitutional symptoms
• Myelosuppression is uncommon

Olsen et al J. Clin. Oncol. 19376-388, 2001
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CTCLs MF/SS Alemtuzumab

• N  OR n ()   CR n () PR n ()   SD n ()  PD
  n ()  
• Blood 7   6 (86)   6 (86)     0 (0)  
    1 (14)     0 (0)  
•   Lymph nodes    11   6 (55)     6 (55)    
  0 (0)     3 (27)   2 (18)  
•   Skin 22 12 (55)   7 (31)   5 (23)  
  5 (23)     5 (23)  
•  Erythroderma 16 11 (69)   6 (38)   5 (31)  
  4 (25)     1 (6)  
•  Plaque/tumors 10 4 (40)   3 (30)   1
  (10)   1 (10) 5 (50)  

Lundin et al Blood 101 4267-4272, 2003
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CTCLs MF/SS Combination Rx

• Combination Therapies - Key Questions to Answer
• Which is the optimal combination?
• Does adding a biological agent hasten remission?
• Are combination therapy remissions more durable
  (FFR)?
• Are combination therapies preferred by patients?
• Will there be any impact on survival?

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Conclusions

• Treatment is directed at palliation
• Pts usually progress from one treatment to the
  next
• Despite decades of experience in the treatment
  of MF/SS, well designed, prospective, controlled
  clinical studies comparing the efficacy of
  various therapies are lacking
• Several new drugs are available for the treatment
  of MF/SS, some of which have favorable toxicity
  profiles
• These drugs may also have applications in other
  malignancies