Bexarotene-Induced T-Cell Immunomodulation and Response in CTCL.

Cutaneous T-cell lymphoma (CTCL) is a group of chronic lymphoproliferative disorders mostly of skin-homing CD4+ T-cells associated with profound suppression of cell-mediated immunity and loss of T-cell reportoire. The immunological effects of current CTCL therapies and their impact on response have not been studied in large samples of patients. Bexarotene is a synthetic retinoic X receptor (RXR) agonist that induces apoptosis in malignant T-cells and has significant clinical activity in CTCL. Bexarotene also exerts multiple effects on normal T-cells. We investigated the in-vivo immunomodulatory effects of bexarotene in patients with CTCL and correlated them with response. 37 patients (pts) with stage IB-III CTCL (33 Mycosis Fungoides, 1 ALCL, 3 pleomorphic small cell) received oral bexarotene (150–300 mg/m²/day) for a median duration of 13 months (range 4–18). Peripheral blood (PB) T-cell subpopulations were measured by multicolor flow cytometry at baseline and during therapy. Circulating CTCL cells were defined as CD4+ CD7− T-cells. 32/37 patients had an elevated PB CD4/CD8 ratio at diagnosis, regardless of the presence of circulating CTCL cells (3/37 pts) and 33/37 pts had a low absolute CD8+ T-cell count (median 98 cells/mm³, normal 150–1000/mm³). After a median time of 6.5 weeks on bexarotene (range 3.5–12) the CD8+ T-cell count had returned within normal range in 26/33 pts and the CD4/CD8 ratio had decreased in 27/32 pts. Responses (defined as Pysician Global Assessment [PGA] of clinical condition) were observed in 24/37 pts (64.8%). Responders had significantly higher peak CD8+ T-cell counts compared to non-responders (median 975/mm³ vs 221/mm³, P=0.002) and lower CD4/CD8 ratios (median 0.8 vs 2.4, P=0.005). At this time 21 pts have relapsed, with median duration of response 9.5 months. A ≥50% decrease in the PB CD8+ T-cell count preceded cutaneous relapse in 17/21 pts (81%) by a median time of 4.5 weeks (range 3–6.5 weeks). Functional analysis (mitogenic response, cytokine secretion, antigenic repertoire) of PB T-cell subpopulations from these pts at baseline and during therapy with bexarotene is in progress. Bexarotene appears to have a profound in vivo T-cell immunomodulatory effect in CTCL pts. The importance of these immune effects for clinical response vis-a-vis direct induction of apoptosis in CTCL needs to be further studied. If these results are confirmed in larger samples, monitoring of PB T-cell subpopulations may provide clinically valuable information in predicting response and relapse.