Sézary Syndrome, Cutaneous T-Cell Lymphoma, and Extracorporeal Photopheresis

The report by Fraser-Andrews et al¹ of their experience with extracorporeal photopheresis (ECP) treatment of patients with leukemic cutaneous T-cell lymphoma (CTCL) who had previously failed treatment with systemic chemotherapy provides valuable information. Since most of the previously reported patients received ECP as an initial systemic therapy, the study patients of Fraser-Andrews et al differ in this quite important way from those whom we and other investigators have treated with this type of active immunotherapy. The median survival of 39 months for the patients in the study of Fraser-Andrews et al did not differ in a statistically significant manner from the median survival of 22 months for their historical control group, and was shorter than the 60 to 100 months in prior reports in which many of the best responders also had clear evidence of clonal malignant cells. The relatively poorer survival data of Fraser-Andrews and colleagues may result from their ECP recipients having been selected from those for whom systemic chemotherapy had not been adequate management.

The reason that we and others have long advised that ECP therapy for patients with CTCL precede immunosuppressive chemotherapy, rather than vice versa, is that the immunocompetence of the patient is prerequisite to the ECP response.² In experimental models of ECP therapy, immunosuppression with corticosteroids completely prevented otherwise potent responses.³

Extracorporeal exposure of malignant cells to photoactivated methoxsalen massively increases their display of tumor antigens by increasing peptide processing and transport.⁴ The best CTCL responses to ECP occur in patients whose CD8 (cytotoxic) T-cell counts have not been suppressed by either prior chemotherapy or disease progression, probably because the CTCL-specific antigens⁵ are weakly immunogenic.

We enthusiastically concur with the suggestion of Fraser-Andrews et al that a multi-institutional, prospective, controlled study be undertaken of the efficacy of ECP for CTCL. Yet it would make little sense to spend several years and great expense conducting a trial of a therapy that would be outmoded by the time the trial concluded. The understanding of the mechanism of ECP has now matured to the point of permitting its logical improvements. At this time, ECP is a rapidly evolving technology, comprehension of its scientific basis finally driving its evolution. For the past 9 months, our group has been conducting a phase I clinical trial of an altered ECP approach that enhances the immunogenicity of the CTCL cells, while simultaneously augmenting numbers of dendritic antigen-presenting cells. If our results remain encouraging, we would be more interested in testing this method in phase III trials than the standard ECP method that it will hopefully replace.

The principal lesson learned from clinical responses to ECP is that selective immunotherapy for patients with CTCL is possible when the capacity of the patient to respond to reinfused or "vaccinating" altered malignant cells remains intact. Sixteen years after the introduction of this treatment, scientifically based improvements of the immunotherapeutic method have finally become possible. It is those potentially improved descendants of ECP that will have sufficient promise to merit the type of multi-institutional trials that Fraser-Andrews and colleagues propose.

The Department of Dermatology at Yale University, which I chair, has received research support from Therakos Inc, the company that manufactures the photopheresis apparatus. In addition, I have been a consultant for Therakos and also have devised the clinical protocol that is, in part, discussed herein.