Predictors of response to extracorporeal photopheresis in advanced mycosis fungoides and Sézary syndrome

Initially developed by Edelson in the 1970s, extracorporeal photopheresis (ECP) is a process by which peripheral blood mononuclear cells (PBMC) are isolated from the circulation by discontinuous leukapheresis, exposed ex vivo to pro-apoptotic doses of 8-methoxypsoralen and ultraviolet A radiation, and then reinfused to the patient (1). ECP was approved by the Food and Drug Administration for advanced cutaneous T-cell lymphoma (CTCL) in 1988 (1), and is now utilized for the treatment of various lymphocyte-mediated diseases, including graft-versus-host disease (GvHD) and solid organ transplant rejection (2–4). Mycosis fungoides (MF) and Sezary syndrome (SS), the major variants of CTCL, are malignancies of clonal T lymphocytes that preferentially infiltrate the skin (5–7). Overt blood involvement is uncommon in clinically early MF, but may be encountered in advanced MF and in SS, which is currently defined as an erythrodermic and leukemic expression of CTCL (8). ECP is often used as a first-line therapy for advanced MF with blood involvement and SS, and the initial pivotal study in which two ECP treatments were administered on consecutive days at 4-week intervals demonstrated that ECP monotherapy induced a substantial improvement in 83% of erythrodermic patients, with 21% of patients eventually achieving a complete response (CR) (1, 9). Of note, in responding patients, the mean time to a positive response was 22.4±9.6 weeks, meaning that ECP must be administered for 32 weeks or more before its effectiveness can be properly assessed. Subsequent studies have shown that the overall response rates to ECP range widely from 31% to 86%, depending on patient selection, treatment frequency, and use of adjunct therapies (10, 11). Despite its utilization for more than two decades, the precise mechanism(s) of action by which ECP exerts its therapeutic benefit on CTCL is not clearly understood nor have reliable predictors of response been identified (12–14). Possible and not necessarily mutually exclusive mechanisms of action include: Induction of an anti-clonotypic immune response against the malignant clone (15). Production of immunosuppressive or immunomodulatory cytokines [e.g. TNF-α, interleukin-10 (IL-10)] by treated mononuclear cells with normalization of the Th1/Th2 immune balance (16–20). Induction of regulatory T (Treg) cells that inhibit neoplastic T-cell growth directly or indirectly via their effect on dendritic cells (21–24). Clinical parameters that have been associated with sustained beneficial responses of CTCL to ECP include short disease durations (early treatment) and clinical improvement before 6 months (9, 25, 26). Laboratory parameters that have been reported to be correlated with favorable responses to ECP include (1) near-normal CD4/CD8 ratios or absolute number of CD8+ cells in the peripheral blood (9, 27), (2) the presence of modest numbers of Sezary cells (28), and (3) relatively low percentages of CD4+CD7− T cells, a phenotype that is often expressed by neoplastic T cells (25). The primary goal of this study was to determine whether the cytokine profile in serum samples obtained at baseline and after 3 months of ECP monotherapy could be used as an early predictor of a clinical response to ECP monotherapy. Previously, we reported that baseline levels of soluble interleukin-2 receptor (sIL-2R) and lactate dehydrogenase (LDH) were not useful in this regard (29). However, sIL-2R and LDH levels did correlate with clinical and other laboratory parameters used to evaluate the response to ECP. A second objective was to evaluate the effect of ECP monotherapy on Th1 and Th2 cytokine levels in the serum. It is widely accepted that the neoplastic T cells of most cases of MF/SS are polarized to secrete Th2 cytokines, and that in advanced CTCL, a Th2 immune profile dominates and contributes to immunosuppression, eosinophilia, and increased IgE levels (30, 31). Our hypothesis was that a shift toward Th1 might occur as an early event in patients responding to ECP as reported for clinically early MF (19). The third goal of this study was to correlate usual clinical and laboratory measures of clinical response to ECP with possible molecular ‘tumor-associated markers’ (STAT3, MICB, and T-plastin/PLS3) in patients with blood involvement. Our hypothesis was that response to ECP monotherapy will result in an early decrease in the level of proposed tumor-associated marker message (mRNA) in PBMC samples obtained during the first 3 months of ECP monotherapy. Lastly, we planned to evaluate clinical and laboratory data during the initial 3 months of ECP treatment in order to identify potential predictors of response.