Treatment of Cutaneous T-Cell Lymphoma: Focus on Relapsed/Refractory Disease This program is...

$Page 1: Treatment of Cutaneous T-Cell Lymphoma: Focus on Relapsed/Refractory Disease This program is supported by an educational grant from Ligand and Clinical.$
Treatment of Cutaneous T-Cell Lymphoma: Focus on Relapsed/Refractory Disease

This program is supported by an educational grant from Ligand and Clinical Care Options, LLC

Pathophysiology and TreatmentJohn A. Zic, MDVanderbilt University Medical CenterNashville, Tennessee

Diagnosis and StagingTimothy M. Kuzel, MDNorthwestern UniversityChicago, Illinois

Treatment of Cutaneous T-Cell Lymphoma: Focus on Relapsed/Refractory Disease

clinicaloptions.com/oncology

Focus on Relapsed/Refractory Disease

First Description of Mycosis Fungoides



Primary Cutaneous T-Cell Lymphoma (CTCL) Mycosis fungoides (MF)

– Most common T-Cell lymphoma of the skin

– Isolated patches, plaques, and/or tumors

Classic histopathologic features

– Superficial dermal infiltrate of malignant lymphocytes

– Cerebriform nuclei within malignant lymphocytes

– Epidermotropism (Pautrier’s microabscesses)

– Early stage lesions include reactive benign T-lymphocytes



Histopathologic Appearance of MF

Upper dermal infiltrate of small lymphocytes with presence of Pautrier’s microabscesses in epidermis



TNM and B Staging of MF*

T (Skin)

– T1 Limited patch/plaque (< 10% BSA)

– T2 Generalized patch/plaque

– T3 Tumors

– T4 Generalized erythroderma

M (Viscera)

– M0 No visceral involvement

– M1 Visceral involvement

B (Blood)

– B0 Atypical circulating cells not present (< 5%)

– B1 > 5% atypical cells, < 1000 atypical cells/mm3

– B2 > 1000 atypical cells/mm3

* Staging should be done at diagnosis only and does not change with treatment effect; provides prognostic information for patients.



TNM and B Staging of MF (continued)

N (Nodes)

– N0 No clinically abnormal nodes

– N1 Clinical abnormal node

– N2 Biopsy performed, not involved with MF

– LN0 normal; LN1 dermatopathic reactive lymph node

– LN2 dermatopathic node with atypical cells (< 6 cells/cluster)

– N3 Biopsy performed, involved with MF

– LN3 large clusters of atypical cells (> 6 cells/cluster) to partial effacement

– LN4 lymph node effacement



CTCL Staging: T1, T2 skin stages

Approximately 50% to 70% of patients with MF/Sézary syndrome will present with isolated patches or plaque type lesions

T1 T2

Kim, Y. H. et al. Arch Dermatol 2003;139:857-866



CTCL Staging: T3 Tumor Stage

Tumors commonly observed with progression from earlier stages

– Rarely present at initial diagnosis



CTCL Staging: T4 Skin Stage

MF/Sézary syndrome; generalized erythroderma

Exfoliative erythroderma

– Significant peripheral blood involvement in > 90% of patients with erythroderma

– Disabling pruritus

Sausville EA, et al. Ann Intern Med. 1988;109:372-382.Schester GP, et al. Blood. 1987;69:1-9.



CTCL Staging: T4 Skin Stage (continued) Poor prognostic features

– PAS-positive cytoplasmic inclusions

– CD4 positive, CD7 negative phenotype

– Large circulating Sézary cells



Staging of CTCL: LN Path stages



Clinical Staging for MF

Clinical Stages T N M

IA T1 N0 M0

IB T2 N0 M0

IIA T1-T2 N1 M0

IIB T3 N0-1 M0

IIIA T4 N0 M0

IIIB T4 N1 M0

IVA T1-4 N2-3 M0

IVB T1-4 N0-3 M1

* The “B” classification does not alter the clinical stage.

TNM Classification*



CTCL: Survival By Stage

Survival for CTCL patient varies according to stage

Little overlap in survival between stages

– Stage IA: no median survival, similar to general population

– Stage IB: 5-year survival ~ 85%

Poor survival in advanced disease

– Median survival for patients with stage IV CTCL: ~ 2.5 years

Kim, Y. H. et al. Arch Dermatol 2003;139:857-866



MF Histopathology

Surface antigen immunophenotyping

– Classic antigenic profile: CD4+, CD8-, CD26-, CD45RO+

– Variable presence or loss of pan T-cell markers CD5 and/or CD7

Early-stage lesions characterized by

– Infiltrating “reactive” CD8+ T-lymphocytes

– Cutaneous dendritic cells (lost upon disease progression)

T-cell gene rearrangement testing to confirm clonality



MF: Recommended Staging Studies

Routine clinical evaluations should include:

– History and physical examination

– Complete blood count with differential

– Examination of blood smear for quantification of atypical lymphocytes (Sézary cells)

– Comprehensive chemistry panel

– Lactate dehydrogenase (LDH)

– Lymph node biopsy if clinically apparent nodes present



MF: Other Staging Studies

Other studies performed in special circumstances or for clinical trials

Bone marrow aspirate/biopsy

– Involvement in patients with advanced disease rarely changes treatment recommendation

Imaging Studies (CT scans)

– Generally of modest utility and rarely positive in early T1 or T2 disease

– Reserved for patients with Sézary syndrome or for quantifying disease stage in patients with tumor stage and palpable adenopathy



Differential Diagnosis of MF

It is important to distinguish between MF and other T-cell disorders involving the skin

– CD30+ cutaneous large T-cell lymphoma

– CD30- cutaneous large T-cell lymphoma

– Peripheral T-cell lymphoma (unspecified)

– Lymphomatoid papulosis

– Subcutaneous panniculitis-like T-cell lymphoma



WHO/EORTC Classification of Primary CTCL

Willemze R, et al. Blood. 2005;105:3768-3785.

CTCL, NK-cell Lymphomas

MF/MF variants and subtypes

Folliculotropic MF Pagetoid reticulosis Granulomatous slack skin

Sézary syndrome

Adult T-cell leukemia/lymphoma

Primary cutaneous CD30+ lymphoproliferative disorders Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis

Subcutaneous panniculitis-like T-cell lymphoma

Extranodal NK/T-cell lymphoma, nasal type

Primary cutaneous peripheral T-cell lymphoma, unspecified Primary cutaneous aggressive epidemiotropic CD8+ T-cell lymphoma (provisional) Cutaneous γ/δ T-cell lymphoma (provisional) Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)



Pathogenesis of MFSkin homing T cells



Membrane Proteins of the Malignant T Cell

CD3 and T-cell receptor

CD4 (TH 2 subtype)

CD45RO (Memory T Cell)

CLA (Cutaneous Lymphoid Antigen)

LFA-1

CD26 (-)/(+)

CD25 (+)/(-)CD7 (-)/(+)

CCR4



Pathogenesis of MF

Girardi M et al. N Eng J Med. 2004;350:1978-1988. Copyright © 2004 Massachusetts Medical Society. All rights reserved.

Epidermotropism

CapillaryExtravasation

Epidermis

Pautrier’s microabscess

Dermis

CLA

CCL17

Endothelial cell

CCR4

E-selectin

T cell

T cell

Langerhans’ cell

TCRαEβ7CCR4

MHC-II

CCL22CD4E-cadherin



CTCL: Prognostic Groups

Low-risk group (most favorable): TNM stages IA, IB, IIA.

– Survival: ~ 12 years

Intermediate risk group: TNM stages IIB, III, IVA with grade LN3 lymph node histopathology

– Survival: ~ 2-3 years

High-risk group (least favorable): TNM stage IVB, IVA with grade 2 years LN4 lymph node histopathology

– Survival: ~ < 2 years

Foss FM, Sausville EA. Hematol Oncol Clin North Am. 1995;9:1011-1019.



CTCL: Skin-Directed Therapy

Topical steroids

Topical nitrogen mustard (NM)

– Mechlorethamine

Topical bexarotene gel

Topical carmustine

Phototherapy

– NBUVB

– PUVA

Radiotherapy

– Total skin EBRT

– Localized EBRT



CTCL: Systemic Therapy

Tretinoin capsules

Bexarotene capsules

Acitretin capsules

Methotrexate

Prednisone/chlorambucil

Interferon

Extracorporeal photochemotherapy

Other biologic modifiers

Denileukin diftitox

Combination chemotherapy



CTCL Treatment Algorithm

Stage IA Stage IB, IIA Stage IIB Stage III Stage IVA, B

Denileukin Diftitox

Electron Beam

Photopheresis ± IFN ± Bex

Photopheresis

UVB

Topical corticosteroids (Class I)

Bexarotene gel

PUVA (± IFN or ± Retinoid)

Nitrogen Mustard

Bexarotene capsules

Chemotherapy or AlloSCT

Chemotherapy or AlloSCT



CTCL: Topical Therapies



Topical Nitrogen Mustard for MF

Mechanism of action: DNA alkylation, possible delayed type hypersensitivity (TH1) response

Aqueous or ointment base, applied to skin once daily

– Continue for 2-3 months after CR (longer maintenance does not decrease relapse rate)

Efficacy in patch/plaque stage MF

– T1 (n = 107) OR 93%; CR 65%; 5-year relapse free rate, 52%

– T2 (n = 88) OR 72%; CR 34%; 5-year relapse free rate, 19%

Kim YH. Dermatol Ther. 2003;16:288-298.Kim YH, et al. Arch Dermatol. 2003;139:165-173.



Topical Nitrogen Mustard for MF

Adverse effects

– Irritant dermatitis < 25% (ointment)

– Allergic contact dermatitis < 66% (aqueous), < 10% (ointment)

– No systemic absorption

– Possible slight increase in nonmelanoma skin cancers

Kim YH. Dermatol Ther. 2003;16:288-298.Kim YH, et al. Arch Dermatol. 2003;139:165-173.



Topical Bexarotene for MF

Mechanism of action: Specific retinoid X receptor ligand that influences critical pathways for cell proliferation, differentiation, and apoptosis

Formulation: 1% gel, applied to affected skin, 1-2 cm margins

– Applied every other day first week, once daily second week, up to 4 times daily as tolerated

Adverse effects

– Irritant “retinoid” dermatitis, 70%– Intervene with dose reduction, mildly potent topical steroids

Zhang C, Duvic M. Dermatol Ther. 2003;16:322-330.Kempf W, et al. Hematol Oncol Clin N Am. 2003;17:1405-1419.



Topical Bexarotene For MF

Efficacy in patch/plaque stage MF:

– Phase I-II trial (n = 67): OR 63%, CR 21%

– Previously untreated patients, OR 75%

– Previously treated patients, OR 67%

– Median onset of response, 5 mos

– Median duration of response, ~ 25 mos

– Phase III trial (n = 50), refractory IA, IB, IIA patients: OR 44%, CR 8%

Breneman et al. Arch Dermatol. 2002;138:325-332.Heald et al. J Invest Dermatol. 2000;114:840 [Abstract 545].



Phototherapy for MF

Mechanism of action: induction of T-cell apoptosis, possibly Langerhans’ cell apoptosis

– Wide-band UVB (WBUVB)

– Narrow-band UVB (NBUVB)

– Psoralens + UVA = PUVA

Baron ED, Stevens SR. Dermatol Ther. 2003;16:303-310.

UVAUVB

290 nm 320 nm 400 nm

Narrow-band UVB311 nm



Phototherapy for MF: Administration

WBUVB: 3X weekly 50–200 milijoules/cm2

NBUVB: 2-3X weekly 1–4 joules/cm2

PUVA: 2-3X weekly 1–8 joules/cm2 + 0.4 mg/kg psoralens (8-MOP) PO 1 hr before treatment

Baron ED, Stevens SR. Dermatol Ther. 2003;16:303-310.



PUVA in MF

Efficacy

– IA: 54/60 (90% CR), 31% relapse

– IB: 88/116 (76% CR), 56% relapse

– IIA: 7/9 (78% CR), 71% relapse

– III: 11/18 (61% CR), ~ 100% relapse

Adverse Effects

– Phototoxic sunburn reactions

– Nausea from ingested psoralens

– Increased risk SCC > BCC (8% to 10% with PUVA)

– Increased risk of melanoma (seen in psoriasis pts treated with PUVA 15 years after first exposure)

Baron ED, Stevens SR. Dermatol Ther. 2003;16:303-310.Herrmann JJ, et al. J Am Acad Dermatol. 1995;33:234-242.



EBRT for MF

Total skin EBRT– 6-9 MeV electrons via linear accelerator– 6 field technique: ant, post, 4 oblique fields– 1.5-2.0 Gy per fraction over 9-10 wks– Total dose: 30-36 Gy

Localized EBRT– Tumors: 9-12 MeV with 2 cm margins– Total dose: 20-30 Gy

Method of action: targets lymphocytes, most radiosensitive cell

Hoppe RT. Dermatol Ther. 2003;16:347-354.Jones GW, et al. Hematol Oncol Clin N Am. 2003;17:1421-1434.



Total Skin EBRT

Hoppe RT. Dermatol Ther. 2003;16:347-354.Jones GW, et al. Hematol Oncol Clin N Am. 1995;9:1057-1076.Jones GW, et al. Hematol Oncol Clin N Am. 2003;17:1421-1434.

Efficacy (n = 561 combined analysis, OR rates 100%)

Stage CR, % Relapse free, % (2.5 yrs)

IA 84-96 64-73

IB 56-81 35-40

llA 63-74 21-37

llB 24-53 7-26

lll 26-50 10-23

15-year progression free survival

Early disease (IA, IB, IIA) ~ 25%

Late disease (IIB, III, IV) < 10%



Total Skin EBRT

Adverse effects

– Acute skin effects: burning erythema, edema

– Chronic skin effects: xerosis, superficial atrophy, telangiectasia, dyspigmentation

– Alopecia, loss of nails (usually regrow)

– Heat intolerance due to the suppression of sweat gland production (usual duration, 6-12 mos)

– Increased SCC and BCC

– Other therapies may play a role

Hoppe RT. Dermatol Ther. 2003;16:347-354Jones GW, et al. Hematol Oncol Clin N Am. 2003;17:1421-1434.



CTCL: Systemic Therapies



Oral Retinoids for MF/Sézary Syndrome Specific retinoid receptor ligands that influence critical

pathways for cell proliferation, differentiation, and apoptosis

Retinoid Daily Dose

Acitretin 25-50 mg/d

Bexarotene* 300 mg/m2 BSA/day

Isotretinoin 1 mg/kg/d

* FDA-approved for CTCL in December 1999




Oral Bexarotene in CTCL

Oral Bexarotene Monotherapy in CTCL

Reference Patients (n) ORR, % CR, % PR, %

Heald P, 2000 4 100

Duvic M et al, 2001 94 45

Stage I, IIA* 54

Stage ≥ IIB† 45

Prince HM et al, 2001 7 71

Talpur R et al, 2002 54 48 4

* Relapse rate: 28%† Median time to relapse: 43 weeks

Kempf W, et al. Hematol Oncol Clin N Am. 2003;17:1405-1419.



Oral Bexarotene in CTCL (continued)

Baseline Week 12

Week 28



Oral Bexarotene for MF/Sézary Syndrome Adverse effects: hyperlipidemia (> 80%): usually requires

treatment with lipid lowering agent

– Triglyceride level of 700-900 mg/dL in patients on treatment warrants therapy interruption for 5-7 days

– Addition of lipid-lowering agent; resume therapy at half initial dose, monitor triglycerides once weekly thereafter

– Initiation of lipid-lowering agent recommended 1 week before starting oral bexarotene

– Diet: reduction of fat/sugar intake

– Initiating with low-dose bexarotene feasible in some patients (eg, those with diabetes)




Oral Bexarotene for MF/Sézary Syndrome Other adverse effects:

– Leukopenia (11%)

– Central hypothyroidism (30% to > 70%): may require thyroid supplementation

– Gemfibrozil contraindicated




Stage IV Disease/Sézary Syndrome



Sézary Syndrome

Characterized by erythroderma, circulating Sézary cells, adenopathy

– Secondary characteristics: alopecia, onychodystrophy, palmar/plantar keratoderma

EORTC suggests: TCRR (+) peripheral blood, CD4/CD8 > 10 for diagnosis of Sézary syndrome.

Prognosis poor: median survival, < 20-36 mos



Photopheresis

Whole Blood

RBC WBC WBC

8-methoxypsoralens

Ultraviolet A

Photoactivation

Return to Pt.

Return to Pt.



Photopheresis for MF/Sézary Syndrome CTCL protocol: one 3-hour treatment on 2 consecutive

days, every 4 weeks

Proposed mechanism of action

– Induces apoptosis of lymphocytes

– Converts monocytes to immature dendritic cells

– Dendritic cells engulf lymphocytes and present tumor antigen to cytotoxic T cells

Zic JA. Dermatol Ther. 2003;16:337-346.



Photopheresis for MF/Sézary Syndrome

Stage Total Patients OR, % CR, %

IB 25 64 28

IIA 25 56 24

IIB 19 53 26

III 28 36 18

IVA 86 51 20

IVB 11 27 9

Skin stage T1 7 57 43




Sézary syndrome 105 43 10

Zic JA. Dermatol Ther. 2003;16:337-346.



Denileukin Diftitox for CTCL

Diphtheria toxin fragments A and B linked to interleukin-2

– Approximately 50% CTCL tumor cells express interleukin-2 receptor

Pivotal study (N = 71) in pretreated patients, most with stage IIB-IVB disease (63%)

– 30% overall response

– Median duration of response, 4 mos

Olsen E, et al. J Clin Oncol. 2001;19:376-388.



Denileukin Diftitox for CTCL: Adverse Events

Olsen E, et al. J Clin Oncol. 2001;19:376-388.Foss FM et al. Clin Lymphoma. 2001;4:298-302.

Acute hypersensitivity reactions (69%): acute; hypotension, SOB, rash, chest pain

– Pretreatment with steroids may improve tolerability, maintain response

Vascular leak syndrome (27%): delayed;hypotension, edema, hypoalbuminemia

Infections (48%)

Lymphopenia (34%)



Chemotherapy for CTCL

Modest response, reserved for relapsed or refractory disease

Duration of response < 6 mos

Some agents show notable activity:

– Deoxycoformycin

– Gemcitabine: phase II trial (N = 32) untreated CTCL, 7 (22%) CR, 17 (53%) PR

– Pegylated liposomal doxorubicin: retrospective analysis (N = 34) CTCL patients,15 CR (DFS 13.3 mo), 15 PR

Kuzel TM. Dermatol Ther. 2003;16:355-361.Pichardo DA, et al. Leuk Lymphoma. 2004;45:1755-1765.Marchi E, et al. Cancer. 2005;104:2437-2441.Wollina U, et al. Cancer. 2003;98:993-1001.



Allogeneic Peripheral Stem Cell Transplant for CTCLReference Patients

(age, yrs)Conditioning

RegimenGVHD

prophylaxisOutcome

Soligo 2003

N = 3 (51-60) Fludarabine, TBI CSA, MMF 3 CR: 18 and 24 mo, 1 dead

d+73

Molina 2003, 2005

N = 8 (21-59) Fludar/Melph n = 4Cyclophos/TBI n = 3Cyclophos/Busulfan

CSA n = 8MTX n = 4MMF n = 6

8 CR: 6 alive (33-106 mo), 2 dead (sepsis)

Guitart 2002

N = 3 (27-39) Cyclophos/Mesna, TBI

CSA, steroid, +/- MMF

3 CR: 15, 52, 60 mo

Masood 2002

N = 1 (37) Cyclophos, TBI MTX, CSA CR: 24 mo

Koeppel 1994

N = 1 (21) Cyclophos, TBI MTX, CSA, steroid

CR: 72 mo

Pichardo DA, et al. Leuk Lymphoma. 2004;45:1755-1765.



Summary of Therapies for CTCL

Skin-directed therapies: highly effective in the early stages of MF

– Relapses common

The challenge: develop systemic targeted therapies with minimal adverse effects capable of inducing meaningful remissions

Current therapeutic goal: do no harm, prevent disease progression

Comparison trials needed to prioritize systemic therapy

Date post:	23-Dec-2015
Category:	Documents
Upload:	imogen-anthony
View:	215 times
Download:	0 times

Treatment of Cutaneous T-Cell Lymphoma: Focus on Relapsed/Refractory Disease This program is...

Documents