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1686 Part XI: Malignant Lymphoid Diseases Chapter 103: Cutaneous T-Cell Lymphoma (Mycosis Fungoides and Sézary Syndrome) 1687

were observed on the clinical trial. Median time to relapse in patients and primary cutaneous anaplastic large cell lymphoma [PCALCL]).
with advanced disease was 56 days. Median time to progression was Response was not correlated with level of CD30 expression at baseline
4.9 months overall, and 9.8 months for stage IIB or higher respond- in MF. Peripheral sensory neuropathy is a significant adverse event
ers. Overall, 32 percent of patients had pruritus relief. The most com- associated with brentuximab vedotin administration. Neuropathy
mon drug-related adverse events were diarrhea (49 percent), fatigue symptoms are cumulative and dose related. Multiple ongoing trials are
(46 percent), nausea (43 percent), and anorexia (26 percent); most were currently evaluating brentuximab vedotin alone or in combination with
grade 2 or lower but those grade 3 or higher included fatigue (5 percent), other agents in relapsed/refractory patients, as well as patients with
pulmonary embolism (5 percent), thrombocytopenia (5 percent), and newly diagnosed disease.
nausea (4 percent). Recombinant Fusion Proteins Denileukin diftitox (DD) is an
Romidepsin is a selective HDACi given as an intravenous infusion. IL-2 diphtheria toxin fusion protein, which had full FDA approval in
Romidepsin was FDA-approved for therapy of CTCL based on a phase October 2008 following a phase III randomized, double-blind, placebo-
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IIB clinical trial documenting an overall response rate of 34 percent, controlled trial. The overall response rate was 37 percent at a dose
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with 6 percent complete responses. The median duration of response of 9 μg/kg/day and 46 percent with 18 μg/kg/day, which was statisti-
was 13.7 months. Toxicities included nausea, vomiting, fatigue, and cally significant (p = 0.002) compared to placebo. Patients receiving
transient thrombocytopenia and granulocytopenia. Romidepsin was 18 μg/kg/day had a progression-free survival of 971+ days and duration
shown to have single-agent clinical activity with significant and durable of response of 220 days. Time to response was 92 days; time to treat-
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responses in patients with CTCL. HDACi may be excellent combi- ment failure was 169 days. Importantly, 45 percent of best responses
national agents, potentiating effects of other therapies, possessing a occurred during cycle 4 and beyond, suggesting that an appropriate
radio- and photosensitizing effects. Several clinical trials are on the way trial of the drug is necessary to achieve optimal responses. All complete
examining potential combinations, including electron beam. 106 responses occurred after four or more cycles. Side effects were numer-
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Interferon-α Interferon-α can be used as a single agent or com- ous, including a capillary leak syndrome, infection, hepatitis, increased
bined with other systemic therapies. The response rate when interferon-α fluid retention, rash, shortness of breath, and flu-like symptoms such
is used as a monotherapy is 50 to 70 percent at doses beginning at 3 to as chills, fever, weakness, bone and muscle pain, headache, nausea, and
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5 × 10 units/day or three times per week, either subcutaneously or vomiting. Cardiac arrhythmias and thrombotic emergencies have been
intralesionally. Toxicity includes acute flu-like symptoms and reported occasionally. Usually, adverse events are most severe during
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fatigue. It is commonly used in combination with other immunothera- the first two cycles, diminishing as the treatments continue. DD manu-
pies (such as extracorporeal photopheresis [ECP] and phototherapy), facturing was discontinued and a new formulation of the same product
but this practice is based on small case series and small prospective is in clinical trials at this time.
studies. It is not clear if combinations truly result in improved clinical Chemotherapy Several agents have been FDA-approved for
outcomes. 10,118,119 therapy of various subsets of MF and SS.
Extracorporeal Photopheresis PUVA can be delivered by an Pralatrexate is a novel antifolate with high affinity for reduced
extracorporeal technique. 120,121 White cells are collected by leukapher- folate carrier-1, which was recently FDA-approved for therapy of trans-
esis, exposed to a photoactivating drug, and irradiated with UVA. The formed MF (tMF). The recommended regimen was identified as 15 mg/
cells then are reinfused into the patient. The effect may be both a direct m a week for 3 of 4 weeks; the response rate was 45 percent. The most
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cytotoxic effect on the tumor cells and an immunologic effect by acti- common grade 3 adverse event (AE) was mucositis (17 percent); the
vating lymphocytes against the tumor cells. Photopheresis typically is only grade 4 AE was leukopenia (3 percent). MF patients were not able
administered every 2 to 4 weeks until clearance of disease. Side effects to tolerate the “lymphoma” dosage of pralatrexate (30 mg/m a week for
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are minimal and may be related to fluid shifts during the procedure. A 6 of 7 weeks) because of intolerable toxicities, including severe mucosi-
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recent retrospective review suggested a survival advantage for patients tis. It was hypothesized that the higher incidence of mucositis was a
treated with ECP and beneficial responses in patients with early stage result of distribution of malignant cells from the skin and mucosal sur-
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MF. 123 faces beyond visible lesions resulting in “localized” tumor necrosis in
Monoclonal Antibodies Alemtuzumab (Campath-1H) is a the skin with collateral damage to surrounding tissues. Administration
humanized IgG1 monoclonal antibody that targets the CD52 antigen. of a single 10 to 15 mg dose of leucovorin 24 hours following pralatrex-
A response rate of 50 percent has been reported in a small cohort of ate infusion, completely abrogated these side effects and allowed ther-
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patients. 124,125 Low-dose alemtuzumab was shown to be safe and effec- apy with 30 mg/m without sacrificing efficacy. 131
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tive in very elderly SS patients. Alemtuzumab effectively depletes Alkylating agents used to treat MF and SS include nitrogen
leukemic cells from blood of these patients. Very low doses on an as mustard topically or systemic cyclophosphamide, or chlorambucil.
needed basis were reported to be effective long-term in SS patients. Response rates of 60 percent, with 15 percent complete remissions,
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Numerous monoclonal antibodies are in clinical trials now as single have been reported. 132,133 Similar results are obtained with methotrex-
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agents and in combinations, including anti–PD-1 antibodies and anti- ate 2.5 to 10 mg/day orally ; bleomycin 7.5 to 15 mg intramuscularly
CCR4 antibody. given twice weekly; and doxorubicin 60 mg/m intravenously given
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Monoclonal Antibody Conjugates Brentuximab vedotin (SGN- once per month. 135,136 Pegylated doxorubicin used in advanced MF
35) is an anti-CD30 antibody conjugated via a protease-cleavable linker has resulted in an overall response of 88 percent. Purine analogues
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to the potent antimicrotubule agent monomethyl auristatin E (MMAE). including fludarabine and pentostatin have response rates as high as
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Following binding to CD30, brentuximab vedotin is rapidly internal- 50 percent. 138–140 Gemcitabine has a similar response rate. Neither
ized and transported to lysosomes where MMAE is released and binds single-agent or multiagent therapy cures MF. Chemotherapy with
to tubulin, leading to cell-cycle arrest and apoptosis. Brentuximab a single agent and polychemotherapy result in a higher incidence of
was recently FDA-approved for CD30+ cutaneous T-cell lymphomas, transformation to large cell lymphoma, which carries a worse progno-
showing durable antitumor activity with a manageable safety profile in sis than the original diagnosis. 142,143 Because responses to therapy are
patients with relapsed/refractory primary cutaneous CD30-positive lym- generally higher after combination therapy, single-agent chemother-
phoproliferative disorders. The overall response rate was 73 percent, apy is used rarely. However, use of multiagent chemotherapy results
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with 54 percent for MF and 100 percent for all other tumor types (LyP in increased immunosuppression and an increased risk of serious

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