Treatment of Relapsing or Recalcitrant Cutaneous T-Cell Lymphoma with Pegylated Liposomal Doxorubicin
Abstract & Commentary
Synopsis: Six patients with biopsy-proven, relapsing or recalcitrant mycosis fungoides were treated with pegylated liposomal doxorubicin (20 mg/m2) monthly. The response rate was 83% with four patients achieving a complete response. Toxicity was minimal.
Source: Wollina U, et al. J Am Acad Dermatol 2000; 42:40-46.
This prospective study enrolled six patients ages 59-78 with mycosis fungoides and adequate hematologic, hepatic, and renal function. All patients had either T2N0M0 (stage Ib) or T3N0M0 (stage IIb) disease. A complete response required the absence of detectable residual disease as determined by a follow-up skin biopsy, irrespective of the presence of post-inflammatory hyperpigmentation. A partial response required either a greater than 50% decrease in the size of lesions or a reduction in more than half of the nodular and plaque-like lesions into macules.
Treatment consisted of a maximum of eight cycles of pegylated liposomal doxorubicin given at a dose of 20 mg/m2 monthly. For these patients with an excellent performance status (Karnovsky index 90% or higher), the toxicity was minimal. Furthermore, the patients were not heavily pretreated. Although all patients had been exposed to either extracorporeal photochemotherapy, PUVA, or selective UV broad-spectrum phototherapy, only one patient had previously received cytotoxic chemotherapy. Four patients had received alpha interferon during extracorporeal photochemotherapy. Although the eligibility criteria were for patients with "recalcitrant" and "relapsing" disease, the patients did not seem particularly refractory with the prior response consisting of either a complete response (1 patient), a partial response (3 patients), or progressive disease (2 patients).
Four patients achieved a complete response documented histologically with a post-treatment punch biopsy. One patient had a partial response and there was one with progressive disease. The time to best response ranged from two to eight cycles.
COMMENT by Kenneth W. Kotz, MD
Mycosis fungoides, as described in the R.E.A.L. classification, is a T-cell non-Hodgkin’s lymphoma characterized by multiple cutaneous plaques or nodules.1 Mycosis fungoides is not considered synonymous with cutaneous T-cell lymphoma (CTCL) by all authors, as the latter term may also include other non-Hodgkin’s lymphomas that involve the skin, such as peripheral T-cell lymphoma and adult T-cell leukemia/lymphoma.1,2
In this study, an impressive response rate, including four of six patients with a pathologic complete response, was seen. However, these patients were not heavily pretreated and some were not refractory to previous therapy. Options available for patients with mycosis fungoides include topical chemotherapy, PUVA, photophoresis (extracorporal photochemotherapy), total skin electron beam radiation, interferon, and a variety of systemic, cytotoxic chemotherapy agents.2 Monoclonal antibodies such as the anti-CD52 CAMPATH-1H have shown responses in mycosis fungoides.3 Activity has also been demonstrated with retinoids including targretin (bexarotene), a high-affinity ligand for the retinoid X-receptor, which was just approved by the FDA.2,4 Finally, a unique approach for CD25-expressing (the IL-2 receptor) CTCLs has been achieved with ONTAK (denileukin diftitox), a combination protein containing diptheria toxin and interleukin-2.2,5
In the title of the article, Wollina and colleagues state "pegylated liposomal doxorubicin" was the product they studied. Caelyx was the brand of encapsulated doxorubicin they used, which is called doxil in the United States. Pegylation is a process by which polyethylene glycol, a hydrophobic polymer, is linked to proteins. This modification results in a pharmaceutical that tends to have a longer half-life and less antigenicity while retaining its biologic activity. For example, oncologists are familiar with oncaspar (pegaspargase), a pegylated form of asparaginase for acute lymphocytic leukemia with an improved therapeutic index over asparaginase. Liposomes are nontoxic, biodegradable, lipid particles which deliver the encapsulated drug compounds to target tissues with less toxicity than the native compound. Examples would include several liposomal amphotericin B preparations which are less toxic than standard amphotericin B, and daunoxome, a liposomal preparation of daunorubicin.
Doxil contains doxorubicin in a carrier system using "STEALTH" liposomes which are formulated with a form of polyethylene glycol, hence, the term "pegylated, liposomal doxorubicin."6 This form of pegylation appears to protect the liposomes from the mononuclear phagocyte system and increase blood circulation time.6 In the United States, doxil is approved for the treatment of ovarian cancer (50 mg/m2 every 4 weeks) and AIDS-related Kaposi’s sarcoma (20 mg/m2 every 3 weeks). In this preliminary study by Wollina et al, a schedule of 20 mg/m2 every month appeared to have potential activity in the early stages of mycosis fungoides.
References
1. Harris NL, et al. Blood 1994;84:1361-1392.
2. Diamandidou E, et al. Blood 1996;88:2385-2409.
3. Lundin J, et al. J Clin Oncol 1998;16:3257-3263.
4. Targretin package insert
5. ONTAK package insert
6. Doxil package insert
Regarding the study by Wollina et al on pegylated liposomal doxorubicin in cutaneous T-cell lympoma, which one of the following statments is true?
a. Cutaneous T cell lymphoma can respond to topical pegylated liposomal doxorubicin.
b. Pegylated liposomal doxorubicin achieved a pathologic CR in some patients.
c. Pegylated liposomal doxorubicin had a higher response rate than doxorubicin.
d. The use of pegylated liposomal doxorubicin at 20 mg/m2 monthly is limited by toxicity.
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