EORTC 21012: Phase II Multicentre Study of Caelyx™ Monotherapy In Patients with Advanced Mycosis Fungoides Stage IIb, Iva and IVb with or without Previous Chemotherapy.

Cutaneous lymphomas consist of a heterogeneous group of diseases that are characterized by a clonal accumulation of lymphocytes in the skin. The estimated incidence is 1–2/100.000 per year. The more advanced stages have a poor prognosis and treatments are usually palliative, such as combination of PUVA with retinoids or recombinant interferon alpha. CHOP or COPBLAM are widely used in analogy to other peripheral T-cell lymphomas, but have severe, sometimes lethal infectious complications and short response duration. Some studies indicated response rates after CHOP chemotherapy regimen are between 40% and 70% in cutaneous T-cell lymphoma (CTCL). However, these studies include patients in various disease stages, that might not necessarily need aggressive treatment and without precise information concerning the CTCL subtype. Therefore, there is an urgent need for multicenter trials designed to test a clearly defined patient population. Pegylated liposomal doxorubicin (PLD, Caelyx™) is an antineoplastic antibiotic with pharmacologic actions similar to those of daunorubicin. PLD provides a longer circulation time and a higher drug concentration in tumors than in normal tissue that could lead to reduced side effects in particular life-threatening cardiotoxicity and neutropenia with infectious complications.

Eligible patients had histologically confirmed Mycosis Fungoides stage IIb, IVa, or IVb, WHO performance status (PS) 0–2, no systemic treatment with steroids and refractory or recurrent disease after at least 2 or more previous therapies. Caelyx 20 mg/m² was administered on days 1 and 15 in a 28-day cycle for a maximum of 6 cycles. The primary endpoint was response rate (RR), defined as patients achieved either complete clinical response (CCR) or partial response (PR). Using the Fleming design with α= 0.1 and β= 0.05 and aiming at a RR = 45% and powered to rule out a RR < 25%, 48 patients who are eligible and started treatment are required. To declare success, a 1-sided 90% confidence interval (CI) for RR should exclude 25% (the rate used in the null hypothesis).

Between November 22, 2003 and July 3, 2009, 9 centers registered 49 patients. All of them were eligible and started treatment. The majority of patients were male (67%), had PS 0, 1 (43%, 53%) and were between 56–65 and 66–75 year old (33% and 31%). The median (range) number of chemotherapy cycles received was 5(1-6) and the majority of patients had relative dose intensity of 90–110% and 70–90% (53% and 35%). Eighty eight percents of patients received prophylactic antiemetics; 84% had PS 0–1 during treatment. There was no Grade 3–4 hematological toxicity; only grade 2 neutropenia (4%), leukopenia (4%) and anemia (4%) were observed during treatment. Grade 3/4 non-hematologic/non biochemical toxicities were cardiac (2%), allergy (2%), constitutional symptom (4%), hand foot reaction (2%), other dermatologic toxicity (6%), other gastro intestinal toxicity (4%) and other infection (4%). One patient (2%) had grade 4 cardiac ischemia. Of 49 patients who were eligible and started treatment, 20 (40.8%) were responders: 3 (6.1%) CCR and 17 (34.7%). The 1-sided 90% CI for the RR is: (31.2%, 100%).

The primary RR endpoint of the study was reached (ie, 1-sided 90% CI excludes 25%). We conclude that Caelyx™ should be considered for further investigation. Caelyx™ has an acceptable safety profile with only a few toxicities and no sepsis observed in this patient population of advanced age. Its efficacy appears promising.

Dummer:Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dhome: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Transgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Schering Plough: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Becker:SheringPlough International: Consultancy. Weichenthal:Schering-Plough : Honoraria, Research Funding.