NEW ORLEANS – A higher baseline percentage of monocytes in patients with Sézary syndrome constitutes a previously unrecognized and potent predictor of clinical response to multimodality therapy incorporating extracorporeal photopheresis.
"Our theory as to why a higher number of monocytes is associated with better outcome is that it possibly leads to increased apoptosis of tumor cells and production of monocyte-derived cytokines, including interleukin-12 and interferon-alpha," Brian Raphael explained at the annual meeting of the American Academy of Dermatology.
Mr. Raphael, a fourth-year medical student at the University of Pennsylvania, Philadelphia, presented a retrospective cohort study analyzing response predictors in 97 patients with Sézary syndrome treated with multimodality therapy, defined as more than 2 months of extracorporeal photopheresis (ECP) plus at least one other systemic immunostimulatory therapy, such as interferon-alpha, interferon-gamma, sargramostim, or systemic retinoids.
This is believed to be the largest-ever such study looking at response markers, according to Mr. Raphael. Sézary syndrome is the leukemic form of cutaneous T-cell lymphoma. The prognosis is poor, with published average 5-year survival rates of only 30%.
ECP has long been considered first-line therapy for erythrodermic patients. At some centers it is employed as monotherapy, but at the University of Pennsylvania, it is typically utilized in a multimodal approach. The rationale is that combining ECP with various systemic immunostimulatory agents enhances antigen presentation, augments antitumor immunity, induces apoptosis through multiple mechanisms, and discourages tumor cell resistance, he said.
In this series, 49 of the 97 patients had stage IIIA or IIIB disease using the 1979 National Cancer Institute classification. The remainder had stage IVA or IVB Sézary syndrome.
One of the most impressive study findings, in the investigators' view, was the 30% complete response rate seen with multimodality therapy. Studies of ECP monotherapy typically cite complete response rates of about 20%, with a complete response being defined in the standard way as resolution of both skin and blood disease.
The partial response rate in the University of Pennsylvania series – defined as at least 50% improvement in both skin and blood disease – was 45%. This made for an overall 75% significant improvement rate with multimodality therapy, compared with a mean 63% significant improvement in previously reported studies of ECP monotherapy.
"These better outcomes suggest multimodality therapy is more effective than monotherapy," Mr. Raphael observed.
More than 50 patient and treatment variables were examined as potential predictors of outcome in the University of Pennsylvania series. The new one to emerge was monocyte percentage at initiation of therapy, which was a median of 9.5% in complete responders, significantly higher than the 7.8% in partial responders and 7.3% in nonresponders and those with progressive disease.
The other three significant predictors of a complete response had previously been identified in other studies. They included a lower ratio of CD4 to CD8 cells – 13.2 in complete responders, 48.7 in partial responders, and 44.2 in nonresponders – and fewer peripherally circulating abnormal T cells at baseline. The mean percentage of circulating CD26-negative lymphocytes was 27.4% in complete responders, 50.7% in partial responders, and 57.2% in nonresponders. Similarly, the mean percentage of circulating lymphocytes that were CD7 negative was 20.1% in complete responders, 36.4% in partial responders, and 41.3% in nonresponders.
Unlike in studies of ECP monotherapy for Sézary syndrome, age at diagnosis, white blood cell count, and disease stage were not significant predictors of a complete response to multimodality therapy in the new study.
Complete responders underwent a mean of 27 ECP sessions, compared with 35.5 in partial responders and 15 in nonresponders.
Mean baseline serum lactate dehydrogenase was 593 U/L in partial responders, compared with 707 U/L in nonresponders. This rather marked difference didn't achieve statistical significance, but that may change with greater patient numbers. In addition to expanding the study size, the investigators hope eventually to identify the most effective multimodality therapeutic combinations for particular patients.
Mr. Raphael said he had no relevant financial disclosures.