Final Results of Phase II Trial of Pegylated Liposomal Doxorubicin (PLD) Followed by Bexarotene (Bex) in Advanced Cutaneous T-Cell Lymphoma (CTCL)

PLD is approved for treatment of Kaposi's sarcoma and concentrates highly in the skin. Overall response (ORR: complete response [CR] + partial response [PR] rates) ranging from 56% to 88%, and CRs from 20% to 44% have been reported with PLD in CTCL patients (pts) without strictly defined response criteria (Cancer 2003; 98: 993–1001; Arch Dermatol 2008; 144: 727–33) Bex is a synthetic retinoid with an ORR of approximately 50% in relapsed/refractory CTCL (J Clin Oncol 2001; 19: 2456–71; Arch Dermatol 2001; 137: 581–93). To clarify the true ORR for PLD and to assess whether the ORR and remission durations can be improved by sequential Bex following PLD, a multi-institutional phase II trial was undertaken for pts with advanced stage/refractory CTCL.

Pts were treated with PLD 20mg/m² IV every 2 weeks for 8 doses (16 weeks) followed by 16 weeks with Bex 300mg/m² orally. Response assessments were performed after 8 (PLD) and 16 weeks (Bex). The Severity-Weighted Assessment Tool (SWAT) (Arch Dermatol 2002; 138: 42–8) was the primary measure of skin response with the Composite Assessment of Index Lesion Severity (J Clin Oncol 2001; 19: 2456–71) and a self-reported pruritus scale as secondary measures. For stage IV pts with baseline lymphadenopathy, CT of chest, abdomen and pelvis was repeated. Sézary cell count and/or flow cytometry were repeated for patients with Sézary syndrome. Pts with complete disappearance of skin lesions on examination were deemed to have a clinical CR (CCR) in skin. A repeat skin biopsy without evidence of disease changed CCR to full CR.

All of the planned 37 pts with stages IV (21 including 7 Sézary syndrome), IIB (10) or refractory earlier stage (6) CTCL have been enrolled and have completed 32 weeks of treatment. Median age was 56 years (27–81). There were 20 males and 17 females. All pts had prior topical treatment with or without irradiation. Fourteen pts had no prior systemic therapy; while23 pts had prior systemic therapies (median 2, range 1–11). Median follow-up for surviving pts is 7.54 months (0.7–41.9). Thirty-four pts were assessable for response (2 withdrew consent, 1 died of disease progression 5 days after initiation of 1^st cycle). For 34 assessable pts: ORR 14/34 (41%: PR 12, CCR 2). Maximum responses were all seen after 16 weeks PLD. Median progression free survival (PFS) is 4.82 months. To date, 18 pts have died of disease progression and 1 patient died of CHF which occurred 3 months after last study intervention. That patient had a pretreatment left ventricular ejection fraction of 60%. Treatment-related grade 3/4 serious adverse events occurred in 9 pts: 4 tumor pain, 2 (grade 3) hand-foot syndrome, 1 infection- unknown ANC- skin (cellulitis), 1 infection- normal ANC- skin (cellulitis), 1 neutropenia.

With strict criteria, PLD ORR is among the highest reported for single agents in CTCL but lower than previously reported. The population contained a high proportion of patients with advanced disease as reflected in the initial stage and the poor survival. Sequential bexarotene did not increase the response rate or duration.

Horwitz:Celgene: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Seattle Genetics: Consultancy; Novartis: Consultancy; Merck: Honoraria; Millennium: Consultancy; Genzyme: Research Funding.