1. Treatment of Cutaneous T-Cell Lymphoma: Focus on Relapsed/Refractory Disease
My name is John Zic, MD, and it is my pleasure to begin this presentation about the treatment of cutaneous T-cell lymphoma, focusing on relapsed and refractory disease.
This program is supported by an educational grant from Ligand and Clinical Care Options, LLC

2. Treatment of Cutaneous T-Cell Lymphoma: Focus on Relapsed/Refractory Disease
Pathophysiology and Treatment John A. Zic, MD
Vanderbilt University Medical Center
Nashville, Tennessee
Diagnosis and Staging Timothy M. Kuzel, MD
Northwestern University
Chicago, Illinois
This slide lists the faculty who were involved in the production of these slides.

3. First Description of Mycosis Fungoides
The first description of mycosis fungoides was published by Dr. Alibert, a French physician in the early 1800s. This slide shows the case report, including a picture of Lucas, the first patient described with mycosis fungoides. In 1806, Alibert originally thought that Lucas had yaws although it was highly unusual for a French soldier in Paris, who had never traveled to the tropics, to have yaws. Later, he coined the term “mycosis fungoides” in a publication in 1832, and the name stuck.

4. 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
In 2005, the World Health Organization (WHO) classified the cutaneous T-cell lymphomas, with mycosis fungoides as the most common subtype. Primary cutaneous T-cell lymphomas are T-lymphocyte malignancies where the skin is the primary organ of involvement. Mycosis fungoides, as described by Alibert, most often begins with patches or small plaques that develop in some protected areas. Some patients develop tumors or even erythroderma.
The classic histopathologic features of mycosis fungoides include a characteristic atypical lymphocyte, which shows a cerebriform nucleus. In addition, these atypical lymphocytes populate the upper part of the dermis and, therefore, a superficial dermal infiltrate is evident. This is often described as a lichenoid infiltrate.
The malignant cells exhibit epidermotropism and often form Pautrier’s microabscesses. Epidermotropism refers to the atypical lymphocytes percolating into the epidermis, the highest layer of the skin.
Early-stage lesions can mimic reactive entities such as spongiotic dermatitis, which may be seen with eczema, or a psoriasiform dermatitis, which may be seen with early psoriasis. As such, patients often need multiple skin biopsies over time to diagnosis mycosis fungoides.

5. Histopathologic Appearance of MF
Upper dermal infiltrate of small lymphocytes with presence of Pautrier’s microabscesses in epidermis
The histopathologic appearance of mycosis fungoides is distinct, with the infiltrate in the upper dermis of mononuclear cells, many of which have bizarre-shaped nuclei. Close inspection shows these lymphocytes percolating into the upper layers of the epidermis and collecting to create a so-called Pautrier’s microabscess, which is depicted in the upper right-hand corner of this histomicrograph.

6. TNM and B Staging of MF* T (Skin) M (Viscera) B (Blood)
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
T, tumor; N, node; M, metastasis
BSA, body surface area
This slide describes the staging criteria for mycosis fungoides. As with most malignancies, there is a T stage, an N stage, and an M stage. The T (skin) stage for mycosis fungoides begins with T1, where patients have limited patches and plaques on the skin, occupying < 10% of the body surface area. Patients with T2 stage disease have more generalized patches and plaques. Patients with T3 disease have tumors present on their skin. These tumors are often > 3-4 cm in size and are often dome shaped or even ulcerated. Some experts believe that an ulcerated thick plaque should be classified as a tumor.
Finally, patients with T4 stage disease have generalized erythroderma, or total body redness. To classify a patient as having T4 disease, he or she needs > 80% of body surface area to be covered with redness.
The B, or blood staging, for mycosis fungoides is unique for this malignancy. The B stage does not factor into the clinical staging, which will be discussed later. B0 indicates that there are no atypical T cells in the peripheral blood. B1 blood stage indicates that there are atypical T cells in the peripheral blood but < 1000 cells/mm3. The B2 skin stage, which is a relatively new designation, means that there are > 1000 atypical lymphocytes per mm3 in the peripheral blood smear.
In addition, the Europeans have included the presence of a T-cell clone, and a CD4 to CD8 ratio > 10 to designate the B2 stage. This will be important later during the discussion of Sézary syndrome where blood involvement is an important criterion.
* Staging should be done at diagnosis only and does not change with treatment effect; provides prognostic information for patients.

7. 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
The lymph node staging of mycosis fungoides is a process in evolution, but presently, N0 signifies that there are no clinically abnormal, palpable lymph nodes. Patients with clinically palpable lymph nodes are often designated as having stage N1.
The designation NP0 refers to patients with lymph node biopsy pathology inconsistent with mycosis fungoides. If a patient has a lymph node biopsy that indicates mycosis fungoides, some authorities recognize the NP1 stage. However, as was mentioned, these lymph node staging recommendations are currently under consideration.

8. 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
For patients who have T1 and T2 skin stages, most have patches and plaques < 10% of their body surface area, or if stage T2, > 10%. Approximately 50% to 70% of patients with mycosis fungoides or Sézary syndrome have isolated patches of plaque-type lesions.
Sézary syndrome is the leukemic variant. These patients, by definition, have T4 disease or generalized erythroderma. However, Sézary syndrome patients will start with scattered patches before evolving into erythroderma.
The patient on the left shows a well-defined plaque with silvery scale. This may appear to be psoriasis to some nondermatologists. However, the fact that the patient has isolated patches that are both ill- and well-defined is much more characteristic of early mycosis fungoides stage T1.
The black patient on the right has both well- and ill-defined hyperpigmented patches, many of which have a hypopigmented variant centrally. These particular hypopigmented patches are often the presenting sign in patients with dark skin, such as black. It is thought that mycosis fungoides may be 1 of the most common skin cancers in black patients. T1 T2
Kim, Y. H. et al. Arch Dermatol 2003;139:

9. CTCL Staging: T3 Tumor Stage
Tumors commonly observed with progression from earlier stages
Rarely present at initial diagnosis
This patient has tumor-stage disease. Tumors are rarely present at the initial diagnosis. If they do, that patient is sometimes designated as having the tumor d’emblée variant of mycosis fungoides. Much more commonly, patients have patches and plaques, which will slowly evolve into tumors as the disease progresses. Patients with tumor-stage disease have a much worse prognosis than patients with thin patches and plaques.

10. CTCL Staging: T4 Skin Stage
MF/Sézary syndrome; generalized erythroderma
Exfoliative erythroderma
Significant peripheral blood involvement in > 90% of patients with erythroderma
Disabling pruritus
This patient has the erythrodermic-skin stage, or T4. This condition can be seen both in patients with mycosis fungoides and the leukemic variant known as Sézary syndrome. Sometimes patients have exfoliative erythroderma, meaning there is widespread scaling of the skin. A majority of patients with erythroderma-skin stage have peripheral blood involvement, meaning that these atypical malignant cells are present in the peripheral blood smear. Often, these patients suffer uncontrollable pruritus, requiring low doses of prednisone, antihistamines, or other systemic agents. Often times, only controlling their disease will improve the pruritus.
Sausville EA, et al. Ann Intern Med. 1988;109: Schester GP, et al. Blood. 1987;69:1-9.

11. CTCL Staging: T4 Skin Stage (continued)
Poor prognostic features
PAS-positive cytoplasmic inclusions
CD4 positive, CD7 negative phenotype
Large circulating Sézary cells
As mentioned, patients with T4 skin stage often have blood involvement. This is a high-power photomicrograph of a hyperconvoluted mononuclear cell (the malignant T cell in this disease) from a peripheral blood smear. On peripheral smear the malignant cells often have PAS-positive cytoplasmic inclusions and, if immunophenotyping is performed, they will often show a CD4+, CD7- immunophenotype. Some patients who have larger circulating Sézary cells will have a worse prognosis.

12. Staging of CTCL: LN Path stages
This slide shows lymph node pathology staging. Patients designated with LN1 and LN2 lymph node stages have reactive lymph nodes with, perhaps, very small clusters of malignant T cells within the lymph node. Patients who have LN3 and LN4 lymph node staging have lymph node involvement with cutaneous T-cell lymphoma. These patients often have much larger aggregates of malignant T cells within the lymph nodes and will often show either partial or total effacement of the lymph node.
Some data suggest that patients with LN4 grade lymph nodes have a worse prognosis than patients with LN3 grade lymph nodes.

13. Clinical Staging for MF
TNM Classification*
Clinical Stages T N M IA T1 N0 M0 IB T2
IIA
T1-T2 N1
IIB T3
N0-1
IIIA T4
IIIB
IVA
T1-4
N2-3
IVB
N0-3 M1
Patients with clinical stage IA mycosis fungoides have patches and plaques over < 10% of their body surface area, with no palpable lymph nodes and no visceral organ involvement. Clinical stage IB mycosis fungoides patients have generalized patches and plaques, but no lymph node or visceral organ involvement.
Patients with IIA disease have patches and plaques on their skin and palpable lymph nodes. However, these palpable lymph nodes, when biopsied, do not show evidence of involvement with mycosis fungoides or cutaneous T-cell lymphoma. Patients with stage IIB disease have tumors without lymph node or visceral organ involvement.
Patients with stage III disease have erythrodermic skin involvement and either no palpable lymph nodes (stage IIIA), or palpable lymph nodes (stage IIIB). However, if lymph node biopsies are performed, they do not show involvement with CTCL.
Stage IVA patients have any skin stage, but have lymph node involvement without visceral organ involvement. And finally, the most advanced stage is IVB. At this stage, patients have any skin involvement, with or without lymph node involvement, but they definitely have visceral organ involvement. The visceral organs most commonly involved with cutaneous T-cell lymphoma include bone marrow, followed by the lungs and liver.
* The “B” classification does not alter the clinical stage.

14. 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
Disease-specific survival curves for patients with CTCL vary by stage. Patients with stage IA disease do not achieve a median survival because their survival is similar to the normal population There is very little overlap of the survival curves based on clinical staging. Therefore, this clinical staging will likely continue to be used in the staging of cutaneous T-cell lymphoma.
Stage IV patients have a very short median survival (approximately 2.5 years). Compare that, for example, with stage IB patients who have not reached their median survival, but have a 5-year survival of approximately 85%.
Disease-specific survival curves for patients with CTCL, broken down by the various stages, are shown here. Patients with stage IA disease do not achieve a median survival because their survival is similar to the normal population. Clearly, there is very little overlap of the survival curves based on clinical staging. Therefore, this clinical staging will likely continue to be used in the staging of cutaneous T-cell lymphoma.
Kim, Y. H. et al. Arch Dermatol 2003;139:

15. 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
Immunophenotyping is important in diagnosing this disease. Immunostains performed on skin biopsies from patients with mycosis fungoides often show a classic antigenic profile of a helper cell (CD4+), along with staining for memory T cells (CD45RO+). Malignant cells often lack staining for CD8 and CD26 markers. In addition, there is a variable loss of CD5 or CD7 immunostaining.
Therefore, a patient with the histologic features of mycosis fungoides and an immunostain pattern showing a CD4+, CD7- T cell infiltrating the epidermis, has strong histologic evidence of mycosis fungoides. However, the clinical features must be combined with the histologic features, and often with the molecular genetic features, before a diagnosis can be solidified.
Early-stage lesions are also characterized by infiltrating reactive CD8+ T lymphocytes, and a few studies suggest that a lack of CD8+ T lymphocytes is indicative of poor prognosis. In addition, cutaneous dendritic cells can be identified on immunostaining that are present to keep the early-stage lesions in check.
T-cell gene arrangement testing can also be performed on the skin biopsies and can certainly be an additional pillar to support the diagnosis of mycosis fungoides. However, there are many reactive skin diseases, such as allergic contact dermatitis, that can also show clonal populations of T cells.

16. 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
Staging studies for patients with mycosis fungoides should include routine clinical evaluations with a complete history and physical examination with special attention to the lymph nodes. In addition, a complete blood count with differential (primarily a manual differential) is indicated because, although it is rare to see blood involvement in early-stage patients, it is important to rule out the presence of Sézary cells or the malignant T cells in the peripheral blood, even in early patients.
However, flow cytometry is not recommended for early-stage patients because their risk of having blood involvement is small, perhaps < 5% to 10%.
A comprehensive chemistry panel will look for evidence of inflammation of the liver, and lactate dehydrogenase is also a good measure of global tumor burden. If a patient has a markedly elevated lactate dehydrogenase level, imaging studies may be indicated to rule out lymphadenopathy or hepatosplenomegaly.
Lymph node biopsy is indicated if there are clinically palpable lymph nodes.

17. 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
CT, computed tomography
Other staging studies are optional for early-stage patients, but should be strongly considered for later- stage patients. These include a bone marrow aspirate or biopsy, especially in patients with a lymphocytosis, or even a monocytosis, on peripheral blood smear.
For reasons that are not clear, the malignant T cells in this disease often have the same size and density of monocytes. And in some patients, monocytosis has been seen as an early indicator of peripheral blood involvement. If patients do have evidence of peripheral blood involvement, it is reasonable to perform a bone marrow biopsy, especially in patients with tumor stage or erythrodermic skin stage.
While important in patients with advanced stage disease, computed tomography scans are rarely positive in patients with early T1 or T2 skin disease. However, patients with Sézary syndrome may benefit from a computed tomography scan of the abdomen and pelvis to rule out hepatosplenomegaly, which may indicate visceral organ involvement. The same could be said for tumor-stage patients, which are more likely to have distant metastases.

18. 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
Differential diagnosis of mycosis fungoides includes benign skin conditions, such as eczematous dermatitis, psoriasis, psoriasiform dermatitis, drug eruptions, and other benign skin diseases. In addition, there are other T-cell disorders that need to be distinguished from mycosis fungoides, including CD30+ cutaneous large T-cell lymphoma, which may include primary cutaneous anaplastic large cell lymphoma, or transformed cutaneous T-cell lymphoma, which is distinct from mycosis fungoides. In addition, there is a CD30­­- cutaneous large T-cell lymphoma that may also present with thick plaques or small tumors. These patients have a very poor prognosis. There are other peripheral T-cell lymphomas, which may have skin involvement and need to be excluded.
Lymphomatoid papulosis is a chronic lymphoproliferative disease where patients will present with crops of papules, some of which resemble bug bites. These papules will undergo spontaneous regression over several months, and is considered by many experts in this field to be a benign disorder. However, it is interesting that the WHO, in 2005, included lymphomatoid papulosis as a variant of cutaneous T-cell lymphoma.
Finally, subcutaneous panniculitis-like T-cell lymphoma can present with subcutaneous masses and nodules, which can mimic mycosis fungoides, and also needs to be excluded.

19. WHO/EORTC Classification of Primary CTCL
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)
In addition to classic mycosis fungoides, there are several variants, including the folliculotropic mycosis fungoides variant, where patients often present with follicular papules, which coalesce into patches, some of which are indistinguishable from classic mycosis fungoides.
Pagetoid reticulosis is a rare variant of mycosis fungoides where patients develop patches or plaques on the palms and soles.
Patients with granulomatous slack skin develop redundant plaques in the axillary and inguinal folds. Approximately 25% of patients with granulomatous slack skin may also develop Hodgkin’s lymphoma. Therefore, close follow-up is recommended.
Sézary syndrome, the leukemic variant, has already been mentioned. Adult T-cell leukemia and lymphoma are included in the WHO/EORTC classification of primary cutaneous CTCL. This is mediated by human T-lymphotropic virus I and II, which is endemic in southern Japan.
The primary cutaneous CD30+ lymphoproliferative disorders include primary cutaneous anaplastic large cell lymphoma, where patients usually present with nodules that may or may not regress, and the previously mentioned regressing papular disorder lymphomatoid papulosis.
Subcutaneous panniculitis-like T-cell lymphoma, which has both an aggressive and a more indolent variant, can mimic mycosis fungoides.
Unspecified extranodal natural killer/T-cell lymphoma is a very rare variant of cutaneous T-cell lymphomas. There is a primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma, which is seen in < 3% of all cutaneous T-cell lymphomas. In addition, there is a very rare gamma-delta T-cell lymphoma, which is a provisional diagnosis. The European Organisation for Research and Treatment of Cancer has described series of patients with CD4+ small- to medium-sized pleomorphic T-cell lymphoma, which often presents with small nodules or thick plaques.
Willemze R, et al. Blood. 2005;105:

20. Pathogenesis of MF Skin homing T cells
The next set of slides will discuss the pathogenesis of mycosis fungoides. The most important teaching point is that this is a disease of skin homing T cells.

21. Membrane Proteins of the Malignant T Cell
CD3 and T-cell receptor
CD4 (TH 2 subtype)
CD45RO (Memory T Cell)
LFA-1
The membrane proteins of the malignant T cell include the CD3 and T-cell receptors on the surface. Mycosis fungoides is predominantly a CD4+ malignant disease. As the disease progresses, the malignant cells begin to secrete TH2 subtype cytokines.
CD45RO is another membrane protein on the malignant cell, and is indicative of a fairly mature T cell. LFA-1 and CCR4 are important in the epidermotropism of the malignant cell, but not as important as the cutaneous lymphoid antigen (CLA).
CLA is a glycoprotein that is expressed on all lymphocytes destined to enter the skin compartment. It is analogous to a zip code that targets a T cell to enter the skin compartment as opposed to the brain, the lung, the spleen, or other visceral organs. CLA binds to E-selectin on the endothelial cells within the skin.
CD25 is present on the surface of approximately 50% of the malignant T cells, whereas CD7 and CD26 are usually not expressed on the malignant T cells in a majority of cases.
CCR4
CD26 (-)/(+)
CLA (Cutaneous Lymphoid Antigen)
CD7 (-)/(+)
CD25 (+)/(-)

22. Pathogenesis of MF Pautrier’s microabscess Epidermis Epidermotropism
T cell
Langerhans’ cell
TCR
αEβ7
CCR4
MHC-II
CCL22
CD4
E-cadherin
Pautrier’s microabscess
Epidermis
CLA
CCL17
Endothelial cell
CCR4
E-selectin
T cell
Epidermotropism
This is a modification of a figure published in the New England Journal of Medicine in 2004, and shows the blue malignant T cells binding to the endothelial cells within capillaries of the dermis. The inset shows E-selectin binding to the cutaneous lymphoid antigen, and CCR4 (a membrane protein on the T cell) binding to CCL17.
Once the malignant T cell binds to these ligands, it begins to tumble along the endothelial wall, eventually extravasating into the dermis. Once the cell is in the dermis, other ligands probably explain the epidermotropism seen with this disease.
The inset shows a Langerhans’ cell binding to the malignant T cell. Specifically, the Langerhans’ cell expresses E-cadherin, CCL22, and MHC class 2 complexes, which bind respectively to an alpha-beta integrin, CCR4, and the T-cell receptor on the malignant T cell.
It is interesting that within a Pautrier’s microabscess, a well-defined Langerhans’ cell can occasionally be seen with its dendritic processes intimately communicating with the malignant T cell. Some experts believe that it is the Langerhans’ cell that may drive early mycosis fungoides and activate these T cells to proliferate in a clonal way.
Dermis
Capillary
Extravasation
Girardi M et al. N Eng J Med. 2004;350: Copyright © 2004 Massachusetts Medical Society. All rights reserved.

23. 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
The low-risk CTCL prognostic group includes the early stages of IA, IB, and IIA. These patients collectively have a median survival of approximately 12 years. The intermediate risk group includes patients with tumor-stage disease, erythroderma, or those with stage IVA, who have LN3 grade lymph node histopathology. The median survival for this group is approximately 2-3 years.
The highest risk group includes patients with visceral organ involvement, stage IVB, and patients with lymph nodes that have lymph node grade LN4 histopathology. These patients have a median survival of < 2 years.
Foss FM, Sausville EA. Hematol Oncol Clin North Am. 1995;9:

24. 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
ERBT, Electron Beam Radiotherapy; NBUVB, narrow-band ultraviolet B radiation; PUVA, PUVA, psoralens and ultraviolet A radiation
Several skin-directed therapies are used to treat CTCL, including topical steroids (particularly high-potency topical steroids), topical nitrogen mustard (also known as mechlorethamine), and topical bexarotene gel (a retinoid). Carmustine, an alkalating agent similar to nitrogen mustard, is also used for early-stage disease.
Phototherapy will be discussed in greater detail in a moment, including how narrow-band UVB therapy and PUVA phototherapy are used to treat this disease.
One of the earliest skin-directed therapies was radiotherapy. X-ray radiation was developed more than 100 years ago. Because of the thick plaques and tumors associated with mycosis fungoides, it became 1 of the first diseases to be treated successfully with radiation therapy. Now either total skin or localized electron beam radiation therapy, which will be discussed later, is used.

25. CTCL: Systemic Therapy
Tretinoin capsules
Bexarotene capsules
Acitretin capsules
Methotrexate
Prednisone/chlorambucil
Interferon
Extracorporeal photochemotherapy
Other biologic modifiers
Denileukin diftitox
Combination chemotherapy
Several systemic therapies are also available for CTCL, including isotretinoin capsules, bexarotene capsules, and acitretin capsules, all of which are retinoids. Methotrexate can be used in some stages, particularly the erythrodermic stage. Prednisone and chlorambucil are 2 agents that are often combined in a palliative fashion to treat patients with more advanced disease, where controlling symptoms is more important than trying to induce remission. Subcutaneous interferon has been used successfully, as has extracorporeal photochemotherapy.
Other biologic modifiers and cytokines have been used in experimental studies. Denileukin diftitox, a US Food and Drug Administration (FDA)–approved therapy for cutaneous T-cell lymphoma, is 1 that will be discussed.
Overall, combination chemotherapy has been disappointing as an approach to treating CTCL.

26. CTCL Treatment Algorithm
Stage IA
Stage IB, IIA
Stage IIB
Stage III
Stage IVA, B
Topical corticosteroids (Class I)
Photopheresis ± IFN ± Bex
Bexarotene gel
PUVA (± IFN or ± Retinoid)
Electron Beam
Bexarotene capsules
The cutaneous T-cell lymphoma treatment algorithm published in Wintrobe’s textbook of Clinical Hematology is shown here. The grid illustrates which therapies are used for each stage of cutaneous T-cell lymphoma.
In the stage IA column, the Class I topical corticosteroids, bexarotene gel, PUVA phototherapy, nitrogen mustard ointment, and UVB phototherapy are listed. All of these therapies are reasonable treatment options in patients with IA disease.
Unfortunately, because of a lack of studies that have compared these therapies, there are no data that suggest the superiority of 1 agent over another. Comparing the response rates of different series of patients is fraught with problems from epidemiologic and statistical approaches.
For stage IB and IIA patients, many of those previously mentioned therapies are quite popular and very reasonable with very good response rates. However, difficult-to-treat IB patients should be offered total skin electron beam radiotherapy (EBRT) if their plaques are very thick and quite generalized. IB may be the first stage to consider using bexarotene capsules, or for the very advanced patient, denileukin diftitox. Also IB would be the first stage to consider photopheresis or extracorporeal photochemotherapy.
Moving from stages IA and IB into the more advanced stages, fewer topical therapies and more systemic therapies are used. Many of these will be discussed in the next several slides.
Denileukin Diftitox
Nitrogen Mustard
UVB
Chemotherapy
or AlloSCT
Chemotherapy
or AlloSCT
Photopheresis

27. CTCL: Topical Therapies
The next section will discuss topical therapies.

28. 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%
Topical nitrogen mustard, a DNA alkylating agent, has been used to treat mycosis fungoides since approximately the 1940s. However, some authorities believe that nitrogen mustard’s induction of a hypersensitivity reaction may also aid in the clearing of mycosis fungoides lesions. Nitrogen mustard is often used in an ointment base, however, some clinicians still use an aqueous formulation applied to the skin once daily.
In general, nitrogen mustard is continued for only 2-3 months after a complete response. If patients only achieve a partial response, they may continue on nitrogen mustard for several years, or until they fail treatment for other reasons.
The efficacy of nitrogen mustard used to treat patch and plaque stage disease depends on the skin stage. However, in a combined analysis of patients at Stanford University, Youn Kim showed that patients with T1 stage disease have an overall response rate of 93%, with a complete response rate of 65%. The 5-year relapse-free rate was 52%.
Patients with T2 disease, on the other hand, had an overall response rate of 72% and a complete response rate of 34%. Also, the 5-year relapse-free response rate was 19%, much less than in T1 stage disease.
Kim YH. Dermatol Ther. 2003;16: Kim YH, et al. Arch Dermatol. 2003;139:

29. 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
The adverse effect profile for topical nitrogen mustard includes an irritant dermatitis in a minority of patients, and an allergic contact dermatitis. For reasons that are unclear, the allergic contact dermatitis is seen most often with the aqueous formulation rather than the ointment formulation.
There are no studies regarding systemic absorption of nitrogen mustard when it is applied to the skin, even to the entire integument.
There may be a role for patients to use nitrogen mustard on only a region of their skin rather than their entire integument. In addition, some studies indicate an increase in nonmelanoma skin cancers in patients that use nitrogen mustard. However, the review of the Stanford experience by Youn Kim did not show a significant increase in nonmelanoma skin cancers.
Kim YH. Dermatol Ther. 2003;16: Kim YH, et al. Arch Dermatol. 2003;139:

30. 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
The next topical agent to be discussed is bexarotene gel. Its unique mechanism of action is to bind a retinoid X receptor (RXR receptor) that requires a partner receptor to affect the transcription of specific genes. These genes influence critical pathways that are important in self-proliferation, differentiation, and apoptosis. Topical bexarotene comes as a 1% gel and is applied to only the affected skin with a 1- to 2-cm margin.
To avoid the adverse effect of an irritant retinoid dermatitis, topical bexarotene gel is applied every other day the first week, once daily the second week, and up to 4 times daily as tolerated. Most patients will only tolerate 3-times-daily application of the 1% gel.
To avoid the retinoid dermatitis, patients can reduce the frequency of application, and midpotent topical steroids can also be used.
Zhang C, Duvic M. Dermatol Ther. 2003;16: Kempf W, et al. Hematol Oncol Clin N Am. 2003;17:

31. 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%
The efficacy of topical bexarotene gel was established in 2 pivotal trials. In phase I and phase II trials of 67 treated or untreated patients, the overall response rate was 63%, with a complete response rate of 21%. A subanalysis found that untreated patients had a higher overall response rate than treated patients.
Topical bexarotene, similar to topical nitrogen mustard, has a median onset of response of approximately 5 months. But the duration of response is an impressive 25 months.
A phase III trial of 50 refractory patients resulted in overall and clinical response rates much less than patients who were either untreated or had failed just 1 treatment.
Interpreting these results, topical bexarotene gel is recommended for patients that are either untreated or who have failed only 1 topical treatment. Due to the irritant dermatitis, bexarotene gel is not recommended in patients with generalized patches and plaques. It would be too irritating to a large surface area of their skin.
Breneman et al. Arch Dermatol. 2002;138: Heald et al. J Invest Dermatol. 2000;114:840 [Abstract 545].

32. 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
UVA, ultraviolet A radiation; UVB, ultraviolet B radiation
The next skin-directed therapy to be discussed is phototherapy, which induces T-cell apoptosis and possibly Langerhans’ cell apoptosis. The Langerhans’ cell is intimately associated with the malignant T cell within the epidermis, which forms Pautrier’s microabscesses.
There are 3 basic forms of phototherapy: wide-band ultraviolet-B (UVB), narrow-band UVB, and psoralen plus ultraviolet-A (PUVA) phototherapy.
The UVB spectrum is nanometers, and the UVA spectrum is nanometers. A narrow wavelength band at approximately 311 nanometers showed efficacy in treating many inflammatory skin diseases without a significant sunburn reaction, which is seen with high doses of wide-band UVB energy. This narrow-band UVB is perhaps the most popular form of phototherapy for all skin diseases. It is very convenient because patients do not have to ingest psoralen before UVA exposure as in PUVA phototherapy. Psoralen is essential to photosensitize patients’ skin cells, perhaps their T cells as well, to the effects of UVA.
UVB
UVA
290 nm
320 nm
400 nm
Narrow-band UVB
311 nm
Baron ED, Stevens SR. Dermatol Ther. 2003;16:

33. 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/cm mg/kg psoralens (8-MOP) PO 1 hr before treatment
Wide-band UVB is used 3 times weekly at doses in the range of millijoules. Narrow-band UVB is used 2-3 times weekly at 1-4 joules. This represents an approximately 100-fold difference in the amount of energy used with narrow-band UVB bulbs vs wide-band bulbs.
Finally, with PUVA phototherapy, patients are treated 2-3 times weekly at doses ranging from 1-8 joules/cm2. In addition, patients ingest 8-methoxypsoralen at a dose of 0.4 mg/kg 1 hour before their UVA exposure.
Baron ED, Stevens SR. Dermatol Ther. 2003;16:

34. PUVA in MF Efficacy Adverse Effects 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)
BCC, basal cell carcinoma; SCC, squamous cell carcinoma
PUVA is the type of phototherapy with the most experience treating mycosis fungoides. The efficacy for early-stage patients is absolutely outstanding, with a 90% complete response rate for IA patients and a 76% complete response rate for IB patients. In IA and stage III patients, the complete response rate decreases.However, even though there is a 90% complete response rate for patients with stage IA disease, a third of those patients will relapse, either while continuing PUVA phototherapy or after stopping it. Although some patients relapse, it is often with a minimal amount of disease that can either be retreated with PUVA phototherapy or with topical agents.
The most notable adverse effect with phototherapy is a phototoxic sunburn reaction. Additionally, the psoralen that is ingested can cause nausea. There is a definite increased risk for squamous cell carcinomas (more than basal cell) in patients treated with PUVA. Perhaps 8% to 10% of patients treated with PUVA are expected to have these nonmelanoma skin cancers. Therefore, in patients who have already had multiple nonmelanoma skin cancers, PUVA phototherapy is not advisable unless the patient has failed multiple other topical therapies.
Finally, the risk of melanoma needs to be clarified in this patient population. Psoriasis patients who had PUVA for ≥ 15 years, or who had > 200 PUVA phototherapy treatments, had an approximately 2-3 times greater risk of melanoma. That risk is unacceptably high considering that the amount of PUVA phototherapy can be controlled and reduced in patients.
Baron ED, Stevens SR. Dermatol Ther. 2003;16:
Herrmann JJ, et al. J Am Acad Dermatol. 1995;33:

35. EBRT for MF Total skin EBRT Localized EBRT
6-9 MeV electrons via linear accelerator
6 field technique: ant, post, 4 oblique fields
Gy per fraction over 9-10 wks
Total dose: Gy
Localized EBRT
Tumors: MeV with 2 cm margins
Total dose: Gy
Method of action: targets lymphocytes, most radiosensitive cell
EBRT, electron beam radiation therapy
The next slides focus on radiotherapy for mycosis fungoides. There are 2 types: total skin electron beam therapy and localized EBRT. Electrons are used in radiotherapy for mycosis fungoides because they penetrate the skin usually < mm, therefore avoiding radiotoxicity to underlying tissues.
The total skin regimen includes using 6-9 mega electron volt electrons, directed at the skin using a linear accelerator. Patients often stand in various poses so the entire skin can be exposed. The total dose is usually gray.
Total skin EBRT is often reserved for patients with extensive plaques or tumor-stage disease. However, there is good data to support using it for erythrodermic patients in addition to other adjunctive therapies.
Localized EBRT can be used to effectively treat a stubborn plaque or patch of mycosis fungoides, in addition to tumors, which often melt away. The method of action is similar to phototherapy in that radiation induces lymphocyte apoptosis.
Also, lymphocytes are quite radiosensitive, as opposed to other white blood cells.
Hoppe RT. Dermatol Ther. 2003;16: Jones GW, et al. Hematol Oncol Clin N Am. 2003;17:

36. Total Skin EBRT 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%
For stage IA patients, an 84% to 96% complete response rate can be expected with total skin EBRT. The relapse-free rate at 2.5 years is approximately 64% to 73%, which is similar to PUVA phototherapy.
For stage IB patients, the complete response rate is 56% to 81%, and for stage III patients, the complete response rate is 26% to 50%. However, the relapse-free rate is only 10% to 23% at 2.5 years.
So, both the complete response rate and the relapse-free rate drop precipitously as the stage increases.
Patients with early-stage disease have a 25% progression-free survival rate at 15 years, compared with patients with late-stage disease who have < 10%.
Nonetheless, total skin EBRT plays an important role in the treatment of patients with generalized thick plaques, or rapidly progressive skin disease. It often gives time to initiate systemic therapies with a slower onset of action.
Hoppe RT. Dermatol Ther. 2003;16: Jones GW, et al. Hematol Oncol Clin N Am. 1995;9: Jones GW, et al. Hematol Oncol Clin N Am. 2003;17:

37. 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
Several adverse effects are associated with total skin electron beam radiotherapy. Along with the acute skin effects such as burning erythema and edema, there are chronic skin effects that included xerosis, superficial atrophy, telangiectasias, and dyspigmentation.
In addition, patients can have their eccrine sweat gland function knocked out for approximately 1 year, putting them at risk for heat stroke.
An increased risk of squamous cell and basal cell carcinomas is debatable. Radiation oncology experts point out that many patients in large clinical trials have had other therapies, such as phototherapy, that may induce nonmelanoma skin cancers prior to radiotherapy.
Hoppe RT. Dermatol Ther. 2003;16: Jones GW, et al. Hematol Oncol Clin N Am. 2003;17:

38. CTCL: Systemic Therapies
The next set of slides discusses systemic therapies for the treatment of cutaneous T-cell lymphoma. The first are the oral retinoids.

39. 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
Oral retinoids bind to retinoid receptors. Bexarotene binds the retinoid X receptor. Acitretin and isotretinoin bind to the retinoic acid receptor alpha-beta. When these receptors are bound by the drug, they induce gene expression of proteins critical to cell proliferation, differentiation, and apoptosis. Of these 3 drugs, only bexarotene is FDA approved for the treatment of cutaneous T-cell lymphoma. As you can expect, some patients may require lower than recommended daily doses due to side effects, or higher doses due to a lack of response.
* FDA-approved for CTCL in December 1999
Zhang C, Duvic M. Dermatol Ther. 2003;16: Kempf W, et al. Hematol Oncol Clin N Am. 2003;17:

40. 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†
Prince HM et al, 2001 7 71
Talpur R et al, 2002 48
The most important clinical trial of patients with cutaneous T-cell lymphoma treated with oral bexarotene monotherapy is the pivotal study published by Madeleine Duvic in It involved 94 patients, many with refractory disease. The overall response rate for the entire cohort was 45%. Patients with stage I to IIA disease had a 54% overall response rate. For patients with more advanced disease, the overall response rate was 45%.
A follow-up study by Dr. Talpur of 54 patients (including some from the Duvic trial) showed an overall response rate of 48%, with a 4% complete response rate.
In the Duvic trial, the relapse rate was 28%. A more impressive statistic is the median time to relapse, which was 43 weeks. To put that into perspective, most patients treated with combination or single-agent chemotherapy have median times to relapse of approximately 8-20 weeks. Therefore, a median time to relapse of 43 weeks is an impressive finding.
* Relapse rate: 28%
† Median time to relapse: 43 weeks
Kempf W, et al. Hematol Oncol Clin N Am. 2003;17:

41. Oral Bexarotene in CTCL (continued)
Baseline
Week 12
These are a series of clinical photographs of a patient enrolled in the Duvic trial using oral bexarotene to treat CTCL. The baseline photo shows a thick plaque/early dome-shaped tumor on the forearm. By Week 12, the thick plaque/tumor had flattened to an erythematous patch and by Week 28, had evolved into a hypopigmented patch. The patch showed no evidence of disease on skin biopsy.
Week 28

42. Oral Bexarotene for MF/Sézary Syndrome
Adverse effects: hyperlipidemia (> 80%): usually requires treatment with lipid lowering agent
Triglyceride level of 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)
The adverse effect profile of oral bexarotene is similar to acitretin and isotretinoin. However, quantitatively, hyperlipidemia is much more common.
Most patients who receive oral bexarotene will have some form of hyperlipidemia, which usually requires treatment with lipid-lowering agents. Hypertriglyceridemia is the most common type of hyperlipidemia seen with oral bexarotene. Triglyceride levels of mg/dL warrant interruption of bexarotene therapy for approximately 5-7 days before reinitiating the drug at a lower dose.
Almost all patients should initiate a lipid-lowering agent 1 week before starting oral bexarotene. In addition, patients are counseled on the importance of a reduction in fat and sugar intake, and, to some extent, carbohydrates. In addition, patients should eat 4 or 5 small meals a day rather than 3 large meals. This reduces the peaks of hypertriglyceridemia seen in normal patients throughout the day.
For some patients who are at high risk for hyperlipidemia (patients with diabetes or familial hyperlipidemia syndromes, etc) initiating low doses of bexarotene is a very reasonable option.
It is worth noting that gemfibrozil is a lipid-lowering agent that is contraindicated in patients on bexarotene. However, all of the statins, long-acting niacin, omega-3 fatty acids, and many others, are safe with oral bexarotene therapy.
In particular, 2-4 g of omega-3 fatty acids with daily meals is recommended when patients begin oral bexarotene. Omega-3 fatty acids usually are available in 1 g capsules over the counter.
Zhang C, Duvic M. Dermatol Ther. 2003;16: Kempf W, et al. Hematol Oncol Clin N Am. 2003;17:

43. Oral Bexarotene for MF/Sézary Syndrome
Other adverse effects:
Leukopenia (11%)
Central hypothyroidism (30% to > 70%): may require thyroid supplementation
Gemfibrozil contraindicated
Other adverse effects of oral bexarotene include leucopenia, which is seen in 11% of patients, and central hypothyroidism, which is seen in 30% to > 70% of patients (may require thyroid supplementation). Central hypothyroidism presents with low thyroid stimulating hormone levels, in addition to low free T4 levels.
Zhang C, Duvic M. Dermatol Ther. 2003;16: Kempf W, et al. Hematol Oncol Clin N Am. 2003;17:

44. Stage IV Disease/Sézary Syndrome
Most patients with Sézary syndrome will develop stage IVA disease with lymph node involvement. The patient depicted in this slide shows total body erythroderma. The peripheral blood smear for this patient shows numerous hyperconvoluted and atypical large cerebriform cells, which represent Sézary cells, or malignant T cells.

45. 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, < mos
Patients with Sézary syndrome show erythroderma, circulating Sézary cells, and often adenopathy. They may also show alopecia, onychodystrophy, and palmar/plantar keratoderma. The keratoderma can be characterized by deep fissures which are exquisitely painful, making ambulation difficult.
The European group suggested the following criteria for blood involvement in Sézary syndrome: In addition to the presence of a peripheral clone of T cells in the blood, they suggest a CD4 to CD8 ratio > 10 to make the diagnosis of Sézary syndrome, which must include blood involvement.
Other blood studies that are helpful include flow cytometry, which can often identify an abnormal population of CD4 cells that have dropped CD7 or CD26.
The prognosis for Sézary syndrome is quite poor, with median survival of usually months.

46. Photopheresis Whole Blood Ultraviolet A 8-methoxypsoralens RBC WBC WBC
One treatment option for patients with Sézary syndrome is photopheresis, which was developed by Richard Edelson in the late 1970s and early 1980s. It was then that the efficacy of PUVA phototherapy in treating patients with mycosis fungoides was established. Dr. Edelson created and helped to engineer a device that could expose a white blood cell fraction of blood to 8-methoxypsoralen and UVA energy, in a sense, performing PUVA phototherapy on peripheral blood.
Patients are connected to a machine with a centrifuge, which separates whole blood into red and white cell fractions. The white cell fraction is then collected and spiked with 8-methoxypsoralen. That mixture is then exposed to UVA energy in a photoactivation chamber. The whole treatment takes approximately 3 hours, and all blood products are put back into the patient.
Return to Pt.
Photoactivation
Return to Pt.

47. 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
The typical CTCL protocol is one 3-hour treatment on 2 consecutive days, every 4 weeks. Adjustments can be made as needed.
One small series showed no benefit to treating patients with mycosis fungoides or Sézary syndrome using a more aggressive protocol of every 1-2 weeks.
The proposed mechanism of action of photopheresis is intriguing. We know that UVA light and 8-methoxypsoralen causes the induction of apoptosis in lymphocytes. In addition, Carole Berger and other researchers at Yale University, in New Haven, Connecticut, have shown that monocytes, as they migrate through the machine, are converted to immature dendritic cells. Immature dendritic cells are perhaps the great antigen-presenting cells of our immune system and are quite adept at engulfing apoptotic cells, including the apoptotic lymphocytes that are being induced by the photopheresis device. Therefore, when these cells are reintroduced into the circulation, the immature dendritic cells can engulf lymphocytes and present tumor antigen to cytotoxic T cells.
This is a proposed mechanism of action for photopheresis, however, further studies will be required to prove this hypothesis.
Zic JA. Dermatol Ther. 2003;16:

48. Photopheresis for MF/Sézary Syndrome
Stage
Total Patients
OR, %
CR, % IB 25 64 28
IIA 56 24
IIB 19 53 26
III 36 18
IVA 86 51 20
IVB 11 27 9
Skin stage T1 7 57 43
Skin stage T2 68 62
Skin stage T3 44 32 16
Skin stage T4
224 58 15
Sézary syndrome
105 10
This is a combined analysis published in Dermatologic Therapy in As of that date, there were 25 patients in the literature with stage IB disease showing an overall combined response of 64% and a complete response of 28%. However, due to the cost of the procedure, it is not recommended as first-line therapy for stage IB disease.
There are also some impressive response rates for patients with stage IIA disease and even IIB disease. However, in patients with skin stage T3 disease, the overall response rate drops to 32%, much lower than the other clinical stages. These data suggest that photopheresis should not be used for treating tumor-stage disease, other than in an adjunctive fashion.
There have been more patients in the literature with erythrodermic skin stage (skin stage T4) treated with photopheresis than any other skin stage. This is because the pivotal trial establishing the FDA approval for photopheresis in 1988 used patients with T4 disease. The overall response rate in the literature for this skin stage is 58%, with a complete response rate of 15%.
Of the 105 patients with Sézary syndrome reported in the literature, the overall response rate was 43%, with a complete response rate of 10%. Also, these response rates refer to the cutaneous response rates and not necessarily lymph node or visceral organ responses.
Nonetheless, these data suggest that the ideal patient to be treated with photopheresis has T4 skin stage with some evidence of blood involvement. In addition, there is enough data to support using photopheresis for IB skin stage in patients that have failed multiple therapies, with response rates in this combined analysis of 62%.
Zic JA. Dermatol Ther. 2003;16:

49. 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
Denileukin diftitox is a systemic treatment approved by the FDA for cutaneous T-cell lymphoma. It is a unique compound that combines fragments of diphtheria toxin A and B covalently linked to interleukin-2. This guided-missile approach to treating cutaneous T-cell lymphoma was developed because approximately 50% of malignant cells in this disease express the interleukin-2 receptor.
Therefore, the theory was that this drug, when introduced intravenously, would home in to tumor cells expressing the interleukin-2 receptor (also known as CD25), enter the skin cell, and the protein fragments of the diphtheria toxin would shut down the protein machinery of a cell and induce death.
In the pivotal study of 71 patients, 63% had advanced-stage disease and had been previously treated with multiple standard therapies. The overall response rate was 30%, and the median duration of response was 4 months, which compares favorably to chemotherapy. However, there was no arm to compare denileukin diftitox to chemotherapy.
Olsen E, et al. J Clin Oncol. 2001;19:

50. Denileukin Diftitox for CTCL: Adverse Events
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%)
The adverse event profile for denileukin diftitox includes acute hypersensitivity reactions seen in two-thirds of patients in the aforementioned trial. Patients can present with acute hypotension, shortness of breath, an urticarial eruption, and even chest pain. However, pretreatment with steroids has been shown to reduce the likelihood of an acute hypersensitivity reaction, and now the standard of care is to pretreat with oral or low-dose intravenous steroids before receiving denileukin diftitox.
In addition, many patients who failed therapy in the original trial were able to maintain the denileukin diftitox cycles because of steroids and, therefore, the response rate would be expected to be > 30%.
An additional adverse side effect of denileukin diftitox includes vascular leak syndrome, which is seen in approximately 27% of patients in the pivotal trial. This is not unique to denileukin diftitox, and can be seen in other cytokine-derived therapies. Patients may present with slowly increasing weight after their first or second cycle of therapy because they will begin to retain more fluid and, therefore, develop pedal or lower extremity edema.
In addition, patients develop hypoalbuminemia, which contributes to worsening edema, and can lead to hypotension or even pulmonary edema. The vascular leak syndrome is often seen between 7-10 days after completing the 5-day cycle of denileukin diftitox, and if mismanaged, can be catastrophic because giving these patients more fluid can lead to more pulmonary edema.
Infections were seen at a rate of approximately 48%. However, lymphopenia was only seen in a third of patients, which compares favorably to chemotherapy.
Denileukin diftitox is given as a one-time infusion over several hours, followed by normal saline, which appears to reduce the risk of vascular leak syndrome. In addition, denileukin diftitox should not be prescribed to patients with albumins much less than 3.0 g/dL. This is also a risk factor for vascular leak syndrome.
Olsen E, et al. J Clin Oncol. 2001;19:
Foss FM et al. Clin Lymphoma. 2001;4:

51. 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
Although most CTCL patients will respond to chemotherapy, it is reserved for relapsed or refractory disease because the duration of response is < 6 months and often < 1 or 2 months. However, there are some agents, such as deoxycoformycin, that show notable activity.
Another is gemcitabine. In a recently published phase II trial of 32 untreated CTCL patients, an overall response rate of 75% was observed. The complete response rate was 22% (7 patients) which is quite favorable. It can be helpful in patients with progressive tumor-stage disease.
Another agent that has shown promise recently is pegylated liposomal doxorubicin. In a retrospective analysis of 34 CTCL patients treated with pegylated liposomal doxorubicin, 30 patients had a response and 15 patients showed a complete response. Even more impressive was the disease-free survival of 13.3 months.
Kuzel TM. Dermatol Ther. 2003;16: Pichardo DA, et al. Leuk Lymphoma. 2004;45: Marchi E, et al. Cancer. 2005;104:
Wollina U, et al. Cancer. 2003;98:

52. Allogeneic Peripheral Stem Cell Transplant for CTCL
Reference
Patients (age, yrs)
Conditioning
Regimen
GVHD prophylaxis
Outcome
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 = 4 Cyclophos/TBI n = 3
Cyclophos/Busulfan
CSA n = 8
MTX n = 4
MMF n = 6
8 CR: 6 alive ( 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)
MTX, CSA, steroid
CR: 72 mo
TBI, total body irradiation; CSA, cyclosporin A; MMF, mycophenolate mofetil; MTX, metrotrexate
Finally, allogeneic peripheral stem-cell transplant shows promise as a systemic-treatment option for CTCL. By contrast, several reasonably sized series showed no long-term benefit to autologous peripheral stem-cell transplant for CTCL.
The first publication was a case report by Dr. Koeppel in 1994 on a patient who was prepped with cyclophosphamide and TBI. The patient experienced a complete response, which, at the time of publication, lasted 72 months. That is impressive for this tumor stage.
The most extensive report, on 8 patients with various conditioning regimens, was published by Molina and colleagues (first in 2003, then updated in 2005). All 8 patients experienced a complete response. At the time of publication, 6 were alive with duration of remissions from months. Two patients, however, died of sepsis, which is the most common cause of death in patients with advanced CTCL.
So, although there are some impressive long-term remissions in the few patients that have been treated with allogeneic peripheral stem-cell transplant, conditioning regimens that may reduce the patient’s risk for infection should be considered. Of course, there is an additional risk of graft vs host disease with allogeneic stem-cell transplants.
None of the patients in the aforementioned studies had graft vs host disease, but as more patients are treated with this modality, that side effect is more likely to be seen.
Pichardo DA, et al. Leuk Lymphoma. 2004;45:

53. 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
Skin-directed therapies should be considered in all early-stage patients before systemic therapies because they are highly effective. However, relapses are common and should be expected. Patients should not be promised a cure with skin-directed therapies. Rather, patients should be promised a high likelihood of control of their disease, which will probably relapse, as do most indolent non-Hodgkin’s lymphomas.
The challenge is to develop systemic therapies that are targeted against the malignant cell that can produce meaningful remissions without an adverse side effect profile worse than the disease itself. As always, do no harm, and avoiding systemic chemotherapy is one way to do no harm to patients with early-stage disease that have not failed skin-directed or other less aggressive systemic therapies.
In addition, comparison trials are definitely needed to help prioritize systemic therapies. This has been exceedingly difficult to arrange, but the community of investigators needs to cooperate to launch comparison trials that will help to understand whether certain therapies should be used before others.