Page 1544 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 85 T-Cell Lymphomas 1371

of both centers in the delivery of this therapy and may not be various topical therapies for early-stage disease. Hoppe et al confirmed
applicable to centers where this approach is less frequently used. For these findings using an ointment-based (Aquaphor or polyethylene
patients with stage IA–IIA disease (see Table 85.5), almost 65%–95% glycol) topical mechlorethamine, which may be associated with a
of patients achieved a CR. Treatment delivered without adjuvant lower incidence of cutaneous sensitivity. A mechlorethamine, 0.02%,
therapies is associated with a relatively high rate of relapse in patients gel preparation has been developed and, compared with the other
of all stages except stage IA. Ten-year relapse-free survival rates at the preparations, has a longer stability and a consistent potency. It is also
two centers ranged from 33% to 52% for this good-prognosis group. quick drying, greaseless, and developed under good manufacturing
However, for stage IB and more advanced disease, 10-year unmain- practices (not compounded in pharmacy). This gel preparation
tained remission rates were only 16% or less. Higher risk patients received FDA approval in 2013 for the treatment of previously
may be “induced” with external beam radiation and then placed on treated stage IA/IB MF after a 12-month phase II multicenter ran-
topical chemotherapy or systemic treatments such as extracorporeal domized trial involving 260 subjects demonstrated noninferiority to
photopheresis for “maintenance.” Still the benefits of therapy may mechlorethamine, 0.02%, ointment. Responses, as measured by the
extend beyond crude estimates of relapse rates or survival. Patients Composite Assessment of Index Lesion Severity (CAILS) score
with tumor lesions, generalized erythroderma, peripheral blood or occurred in 58.5% of the patients on the gel arm and 47.7% of the
nodal involvement, and even visceral spread can be successfully pal- patients receiving the ointment. Time to 50% RR was significantly
liated with electron beam radiation therapy as well. Side effects, earlier with the gel (26 weeks vs. 42 weeks; p < .01). Patients who
however, can be occasionally extreme, including scaling, dryness of tolerated therapy without achieving a CR were enrolled in a 7-month
skin, erythema, edematous extremities, telangiectasia formation, skin extension study assessing the efficacy and tolerability of a mechlor-
ulceration, and hair or sweat gland loss (usually transient but occa- ethamine, 0.04%, gel. Twenty six (26.5%) of the 98 patients who
sionally permanent). Careful radiation dosimetric techniques are received treatment achieved confirmed CAILS responses including
required to ensure adequate skin treatment without excessive organ six CRs, and an additional 14 patients (14.3%) had their first response
toxicity. We do not use electron beam radiotherapy early in the course at their final visit, yielding an unconfirmed RR of 40.8%.
of the disease because other topical therapies have been developed For early-stage disease, topical mechlorethamine offers an efficient,
that yield similar RRs with less potential toxicity. The long duration convenient (outpatient treatment), and relatively inexpensive treat-
of remissions observed in patients with stage IA disease does not ment option. Side effects consist of delayed hypersensitivity in
equate with cure, because their life expectancy is essentially the same approximately 35% of patients, although ointment-based solutions
as age-matched controls, and these patients may simply have indolent appeared to offer a reduced risk for allergic contact dermatitis. Once
biology. One group has reported their experience with multiple hypersensitivity develops, patients can be desensitized by injecting
courses of therapy. Fifteen patients with relapsed MF a mean of 41 minute daily doses of mechlorethamine over a period of several weeks.
months after the initial course of electron beam therapy were retreated. This should be done only in a medical setting with appropriate
All patients had received intervening therapies for disease control. anaphylaxis precautions observed. Other investigators had difficulty
Eleven of the 15 had a CR with their first cycle of radiation. The replicating the results using this risky procedure, and topical desen-
second course achieved six CRs and nine PRs. The median duration sitization has become much more common. Constantine et al propose
of the initial CR was 11 months. The median duration of CR to the that therapy should be transiently discontinued until clearance of the
second course of therapy was only 3 months, suggesting radiation allergic dermatitis is achieved (using topical steroids if necessary).
resistance had developed between the first and second cycles in many Then 0.01–0.1 mg per 100 mL of the drug should be applied daily
patients. In general, toxicity was thought to be tolerable. for 1 week. If this dilution is tolerated, the dosage is doubled weekly
until the dose achieved is often identical to the initial concentration
that induced the hypersensitivity.
Topical Drug Therapy Some clinicians, however, believe that a mild hypersensitivity
reaction may have beneficial antitumor effects. Ratner et al previously
The initial therapies for MF focused on treatment of the skin disease. demonstrated that plaque lesions of MF cleared when exposed to
Patients have long been known to benefit from the application of topical doses of 2,4-dinitrochlorobenzene, a known universal inducer
topical steroids. Zackheim et al reported a 63% complete RR with of delayed hypersensitivity responses. Anergic individuals failed to
twice-daily applications in stage T1 patients but only a 25% complete improve. Other known sensitizing agents yielded similar but less
RR in stage T2 patients. Novel approaches by dermatologists to apply dramatic responses. Some hypersensitivity may be beneficial; the
chemotherapy topically to avoid systemic therapy complications have generalized erythroderma and pruritus are usually poorly tolerated
also been devised. Mechlorethamine hydrochloride was the first when severe, however, and some alteration in therapy is required.
topical agent evaluated to demonstrate efficacy in MF. The solution An increased risk for secondary skin cancers in patients receiving
used for topical application contains 10–20 mg of mechlorethamine long-term mechlorethamine has been observed. Some physicians have
dissolved in 50–100 mL of tap water (no vesicant activity at this low expressed concern regarding the safety of family members or health-
concentration). Although several methods may be used for adminis- care workers secondarily exposed to the topical solutions. Home
tration, self-administration at home to the entire skin surface is treatment with topical mechlorethamine has been shown to result in
preferred. The concentration may need to be varied depending on aerosolized drug levels, which may result in mucous membrane or
patient tolerance and sensitivity. The time to initial response is usually ocular irritation. However, we are unaware of any documented
short, approximately 1–2 weeks, but long-term application is usually adverse outcomes and believe this to be a theoretical concern rather
required to obtain the maximum response. than a practical one.
Several large studies have been completed demonstrating the Several other topical agents have been tested and shown to be of
benefit of mechlorethamine, especially in early-stage disease. One by benefit in the treatment of MF, including cytarabine, dianhydroga-
Vonderheid et al reported their experience with topical mechloretha- lactitol, dacarbazine, guanazole, teniposide, hydroxyurea, thiotepa,
mine and found that it compared favorably with results achieved with and methotrexate. However, topical carmustine is the only one of
electron beam treatment. CRs were seen in 80%, 68%, and 61% of these agents that has demonstrated clinical use. A stock solution is
patients with limited plaque, extensive plaque, and tumor lesions, created with 300 mg carmustine in 150 mL of 95% ethanol (suffi-
respectively. The corresponding median duration of remissions was cient for 30 days of treatment). The patient then adds 5 mL of the
in excess of 15, 5, and 12 months, respectively. It is difficult to draw 0.2% stock solution to 60 mL of room-temperature tap water. This
definite conclusions from these data, because many patients included solution can then be applied to the general body surface, with the
in the analysis also received intravenous mechlorethamine or metho- exception of the head, genitals, palms, soles, and intertriginous zones,
trexate, and some may have received radiation therapy. Several unless involved by disease. Applications are planned to occur daily
patients have relapsed as long as 8 years after the completion of for 2–6 months, if necessary. Brief exposures to double-dose solution
therapy, suggesting that follow-up times must be long to compare can be used for resistant disease. Results in 188 patients with patch