Low Dose Bexarotene and Ultraviolet A Photochemotherapy (PUVA) In a Prospective Phase II Clinical Study for Refractory and/or Resistant Cutaneous T Cell Lymphomas (CTCL)
Authors: Rupoli Serena , Pimpinelli Nicola , Goteri Gaia , Canafoglia Lucia , Picardi Paola , Brandozzi Giuliano , Pulini Stefano , Federici Irene , Scortechini Anna Rita , Tomassetti Simona , Albani Lisa , Da Lio Lidia , Giangiacomi Mirella , Leoni Pietro 
Published: October 2019

Abstract
Abstract 3953
Oral bexarotene, a novel retinoid that selectively activates retinoid × receptors, is approved for the treatment of cutaneous manifestations of refractory or relapsed cutaneous T cell lymphomas (CTCL) as monotherapy. Phase II/III trials have demonstrated a greater than 50% response rate in patients with all stages of CTCL who were refractory or intolerant to the previous therapy but the recommended bexarotene dose of 300 mg/m2/day is associated with significant side-effects. Novel studies are looking for synergistic therapies combining lower bexarotene doses in order to reach the same or even better outcomes while avoiding a negative impact on the quality of life. Early studies with bexarotene and psoralen plus ultraviolet A photochemotherapy (PUVA) show promise. Synergy between bexarotene and PUVA may derive from retinoid-induced reductions in epidermal thickness, which consequently improves UVA penetrations, and/or from retinoid-specific enhancement of immune functions. The aim of this study was to assess the efficacy and safety of a 2 stage-protocol (induction and maintenance) with low dose bexarotene (Targretin) and PUVA in refractory and/or resistant patients with Mycosis Fungoides (MF) and Sézary Syndrome (SS).
A prospective, phase 2 clinical study was conducted between February 2007 and May 2010 by two Italian academic hospital centers. We enrolled 15 patients with stages I through IV MF/SS; all patients had failed PUVA or several systemic regimens. Response to treatment was assessed with clinical endpoints such as remission of symptoms (pruritus, pain, sleep disturbance) and signs (erythema, scaling, thickness of plaques, presence of nodules, tumours, peripheral lymphadenopathy). Complete remission (CR) was defined as the disappearance of all clinical evidence of disease for at least 4–6 weeks, partial remission (PR) as 50% or more decrease in extent or severity of disease. Overall response (OR) rate was defined as the combination of CR/PR. Patients with MF/SS were started with bexarotene (150 mg/day) and PUVA (three times weekly). Increments of bexarotene to a maximum of 300 mg/day were scheduled. Patients who achieved CRs and PRs during the induction remained on the same dose in the maintenance period, whereas the frequency of PUVA was gradually reduced. A preventive therapy to lower triglycerides and elevated thyroid hormone levels in the blood, was administered in all cases; therapeutic dietary and lifestyle changes were often recommended.
Primary endpoint were OR rate at the end of induction and maintenance; secondary endpoints were safety and event-free survival (EFS). Kaplan-Meyer method and long-rank test was used for statistical analysis.
All 15 patients (8 M and 7F) were evaluable for response; ten patients had early-stage (IB) and 5 had advanced stage (2 IIB, 1 IIIA, 1 IIIB, 1 IV). The median age was 68 years (34-81). The OR rate was 93% with 33% CR after induction period and 93% with 47% CR at the end of the protocol. A response was observed even in 1 case with SS and in 2 cases with MF in large cell transformation. Significantly, patients treated previously with PUVA monotherapy achieved better and faster CR compared with those treated with more than one systemic therapy (83% and 22% respectively; χ2 test, P=0.041; median time to maximal response 4 weeks and 8 weeks respectively, P=0.007). Median EFS at 37 months, for the whole group was 27 months. All patients have been closely monitored for adverse events during treatment; 2 of 15 patients (13%) had mild grade I-II asthenia, hypercholesterolemia and central hypothyroidism, 2 patients developed elevations of CPK (grade 3). With regard to hematologic toxicity, leukopenia was mild (grade I) and occurred in 3 patients (20%).
In conclusion, our study have demonstrated a greater than 90% response rate in patients with all stages of CTCL refractory or intolerant to the previous therapies; the efficacy is more pronounced in patients previously treated with PUVA monotherapy. Starting treatment at lower dose of bexarotene followed by dose escalation may improve the efficacy and safety of both bexarotene and PUVA. Moreover the additional maintenance phase seems to improve the OR and length of remissions.

Disclosures:
Leoni: Celgene: Honoraria.