Optimal Combination With PUVA: Rationale and Clinical Trial Update

Cutaneous T-cell lymphoma (CTCL) is relatively benign in its early stages, but survival rates decrease dramatically as the disease progresses. As no curative therapies are currently available, the goal of therapy is preventing or delaying progression from early disease stages while minimizing long-term toxicity. No single agent, including psoralen plus ultraviolet A (PUVA), can control disease progression fully, so combination therapy is needed to improve response rates. In addition, low-dose combination therapy may improve treatment safety and tolerability. A combination of PUVA and interferon (IFN)α in early disease has been shown to be effective and well tolerated. Likewise, small studies of PUVA and bexarotene (Targretin) indicate good efficacy for this combination. Reduced doses of these combinations may also be effective as maintenance therapies following complete remission. Other treatment combinations shown to be effective in early disease stages include bexarotene with IFNα, and bexarotene with denileukin diftitox (Ontak). In advanced stages of CTCL, liposomal-encapsulated doxorubicin or extracorporeal photopheresis may be combined with bexarotene or IFNα.

The class of cutaneous lymphomas comprises a variety of diseases. By the new World Health Organization/European Organisation for Research and Treatment of Cancer classification,[1] the largest single disorder is mycosis fungoides (MF), which makes up 50% of cases.[2] The next largest proportion of cases (20%) consists of the so-called CD30 lymphoproliferative diseases. Some of the genetic mechanisms of the disease process in cutaneous T-cell lymphoma (CTCL) have now been well characterized (see the article by Sterry in this supplement), and it is known that there is a clear shift in patients' cytokine profiles during disease progression-from Th1- to Th2-dominating.

In the management of CTCL, there is therefore a rationale for using retinoids and rexinoids, which increase Th1 cytokines,[3,4] and interferon (IFN)α, which can rectify the imbalance between Th1 and Th2 cytokines.[5] Furthermore, resistance to activation-induced cell death and bystander cytotoxicity via the Fas/Fas ligand pathway are implicated in the pathogenesis of CTCL.[6] However, bexarotene (Targretin) has been shown to induce apoptosis as a mechanism of therapy in CTCL.[4] In addition, psoralen plus ultraviolet A (PUVA) acts as deep as the middermis, and plays a key role in the reduction of Langerhans cells and the presentation of antigens in the skin.[7]

In its early stages, CTCL is a relatively benign disease, but once it progresses to stage IIb and to lymph-node involvement there is a dramatic reduction in patients' 5-year survival.[8] At present, there are no curative therapies available for CTCL, and early aggressive therapy does not appear to increase patients' response rates or survival time. The therapeutic goal is therefore to prevent progression from early disease, in which survival rates are good, to advanced-stage disease, which has a poor prognosis. In addition, therapy should aim to minimize cytotoxic effects against normal lymphocytes and to maintain good long-term treatment tolerability. This is best achieved using stage-adapted therapy. As no curative therapies for CTCL are available, long-term treatment with meaningful combinations is mandatory to maintain recurrence-free survival.

Many different therapies are available for the treatment of CTCL-both skin-directed and systemic. This review will focus mainly on combination therapy with PUVA, IFNα, and bexarotene.

Rationale for Combination Therapy for CTCL

There is currently no single agent available that is potent enough to control CTCL; overall response rates to monotherapies are about 50% to 60%. For example, among 104 patients with MF given PUVA monotherapy, 63% (66/104) initially responded to this therapy and experienced complete remission. Over a median follow-up of 94 months, the recurrence rate was 32% (33/104).[9] Thus, the main conclusion of this study was that PUVA, though effective, was not sufficient to control the disease. PUVA has, however, been shown to play a critical role in maintaining response following a complete response to total-skin electron beam therapy.[10]

Combinations of agents with different modes of action may increase patients' response rates and, if the therapies are given at low doses, this may minimize the toxicity of each individual treatment. Moreover, there are some indications that combining drugs may prevent the progression of disease to extracutaneous T-cell lymphoma involvement. Thus, the combination of topical and systemic treatment may consolidate remission and allow continuous therapy with an acceptable side-effect profile.

PUVA Plus IFNα or Retinoids in Early-Stage CTCL

The most common treatment combinations for use in early CTCL (stages I-IIa) are PUVA with either IFNα or bexarotene, although alternatives include other retinoid compounds and denileukin diftitox (Ontak) (Figure 1A). A review of studies with IFNα monotherapy in a total of 207 patients with MF or Sézary syndrome (SS) reported an overall complete response rate of 52%, but the rate was only slightly higher (60%) in 102 patients who received this drug in combination with a retinoid.[11] A considerably higher complete response rate of 82% was achieved when IFNα was combined with PUVA in a multicenter study of 98 patients with stages I and II MF, or small- to medium-sized pleiomorphic T-cell lymphoma. This was superior to the combination of IFNα and retinoids, investigated in the same study, for which the complete response rate was 49%.[12] Nevertheless, the IFNα plus retinoid combination produced a marked response in some patients.

A comparison of PUVA plus IFNα vs PUVA alone in 96 patients with CTCL stages I and II showed that the combination therapy produced a complete response rate of 80%, compared with 72% for PUVA alone.[13] Although this treatment difference was not significant, the cumulative dose of ultraviolet A was significantly lower for the combination therapy than for PUVA alone, which is important in long-term treatment. Moreover, the recurrence-free time was 113 weeks for PUVA plus IFNα compared with 56 weeks for PUVA alone (Figure 2). Similar results were reported in a study of 89 patients with stage Ia-IIa MF treated with IFNα, 6-18 MIU, plus PUVA over 14 months.[14] The rate of complete remission was 84%, and continuous remission was seen in 20% of this group. The combination of IFNα plus PUVA therapy is therefore a safe and effective treatment for early disease stages. This combination therapy could both reduce treatment dose, and therefore toxicity, and increase the recurrence-free time, compared with monotherapy.

The other main group of systemic therapies used in CTCL is the rexinoids. When given as monotherapy in patients at all disease stages, bexarotene produced response rates of about 50%.[15,16] In addition, several small studies have demonstrated the efficacy of bexarotene in combination with other therapies.

Case history data are available from treatment of a 55-year-old woman with MF in whom combination therapy with PUVA twice weekly and bexarotene at 375 to 225 mg/d resulted in stable disease.[17] In a case series of eight patients at MF disease stage Ia or Ib treated with bexarotene at the low dose of 75 mg/d (300 mg/d in one patient) and PUVA at 0.5-1.5 J/cm², which could be increased to a maximum of 15 J/cm², there was a clinical complete remission rate of 63% and an overall response rate of 75%.[18] Several other case series that show promising results for this combination have been reported,[19] and further studies are required.

Other Combination Therapies

A range of other combination therapies in early-stage CTCL has also been investigated. Bexarotene and denileukin diftitox act synergistically, as the immunomodulatory capacity of the retinoid enhances the expression of the high-affinity interleukin (IL)-2 receptor and increases susceptibility to denileukin diftitox.[20] Among 14 patients with CTCL stages I-IVb treated with bexarotene at 75-300 mg/d combined with denileukin diftitox at 18 µg/kg/d three times every 21 days, the overall response rate was 67%, and tumor cell IL-2 receptor upregulation was reached with bexarotene doses of ≥ 150 mg/d.[21]

A small study investigated the efficacy of bexarotene at 150 mg/d and low-dose IFNα at 1.8-2.4 MIU three times weekly, in two patients with erythrodermic CTCL and one with follicular MF. The authors concluded that this combination was well tolerated and induced rapid improvement in patients.[22] A larger study in 22 patients with a wide range of CTCL stages Ib-IV was published recently. They were given bexarotene at 300 mg/m² for 8 weeks initially and, for those who showed less than a complete response, IFNα at 3-5 MIU three times weekly for 8 weeks was added. The overall response rate was 74%. The main conclusion of this study was that the major response rate was similar to that produced by bexarotene alone and that the clinical usefulness of this approach is limited by the inconvenience of the IFN injections. However, it is possible that more positive results might have been obtained had treatment been initiated with the combination, rather than introducing the treatments in this stepwise manner.[23] Bexarotene, with its excellent tolerability, offers several opportunities for combination treatment modalities (Figure 1B).

Combination Therapy in Advanced-Stage CTCL

In advanced-stage CTCL, possible agents for combination with bexarotene or IFNα include cytotoxic therapy with liposomal-encapsulated doxorubicin. This combination is currently used mainly as a "crisis intervention," employing just two or three rounds of therapy. A small phase II study with liposomal-encapsulated doxorubicin showed promising results.[24]

Another possible therapy for CTCL stage III or SS is extracorporeal photopheresis, which can be combined with IFNα and/or bexarotene (Figure 1C). When used alone in 448 patients with SS, the overall response rate to photopheresis was 61%, with a complete response rate of 19% in these patients with severe disease.[25] Data are also available from five patients with SS, all of whom received monthly photopheresis in combination with: IFNγ at 1.6 MIU four times weekly plus bexarotene at 150 mg/d (two patients); bexarotene at 150 mg/d (one patient); or IFNα 2b at 2.4 MIU three times weekly plus bexarotene 150 mg/d (two patients). These treatments produced three complete remissions and two partial responses, which was a favorable result for these treatment combinations in patients with severe disease.[26]

Maintenance Therapies for CTCL

For patients with CTCL who achieve complete remission, there are currently no recommended maintenance therapies. Following therapy with PUVA plus IFNα, a possible approach would be to use "homeopathic PUVA" at home or low-dose IFNα (3 MIU). Likewise, following therapy with PUVA plus bexarotene, maintenance therapy could comprise homeopathic PUVA or low-dose bexarotene (150 mg/total body weight/d). If PUVA is to be continued following a complete remission, the interval frequency should be reduced gradually until it is given once per month provided that the patient remains in complete remission. In this way, small doses of PUVA can be used in the long term.

Conclusions

A number of different therapies and treatment modalities are currently available for the management of CTCL, to be used alone or in combination. These treatment options should be tested systematically and used judiciously so that in this chronic disease that requires long-term treatment of elderly patients, treatment efficacy is maintained and long-term toxicity is minimized.

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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