Response to Ontak Leads to Improved QOL in CTCL

MIAMI BEACH, Florida—Cutaneous T-cell lymphomas (CTCL) often cause severe facial disfigurement that adversely affects a patient’s quality-of-life. A new fusion protein, DAB389IL-2 (denileukin diftitox, Ontak), has produced significant response rates in heavily pretreated relapsed CTCL patients and improved quality of life, Madeleine Duvic, MD, said at the American Society of Hematology (ASH) annual meeting.

“This is a very difficult disease to treat, but this new therapy targets the malignant T cells rather than the entire immune system as do traditional myelo-suppressive chemotherapy regimens,” said Dr. Duvic, professor of medicine and dermatology, the University of Texas M.D. Anderson Cancer Center.

Approximately 800 new cases of CTCL are diagnosed annually in the United States, and currently there is no cure, although many patients live for many years with palliative care. Dr. Duvic reported that one patient who received DAB₃₈₉IL-2 more than 8 years ago is still alive and in remission.

DAB₃₈₉IL-2 combines the receptor-binding domain of interleukin-2 (IL-2) with diphtheria toxin. It targets the IL-2 receptors in activated T cells expressing CD25. The IL-2 receptors take up the agent, the toxin is released, and the cells die due to inhibition of protein synthesis. The agent (manufactured by Seragen and marketed by Ligand Pharmaceuticals) recently received FDA approval for use in CTCL, based on the study described by Dr. Duvic.

The study enrolled 71 patients at 20 US centers. Eligible patients had stage IB-III disease and at least four prior therapies or stage IV disease and one or more prior therapies. Also, more than 20% of lesional lymphocytes had to stain positive for CD25.

Patients received an intravenous infusion of DAB₃₈₉IL-2 over 15 to 30 minutes for 5 days at a dosage of either 9 or 18 µg/kg/day. Courses were repeated every 3 weeks for up to eight cycles, providing there was no evidence of progressive disease or toxicity.

Dose adjustments were not allowed, but patients could delay courses for up to 1 week. Dr. Duvic said that the protocol was very strict, and in the real world, doses would be adjusted to allow for toxicities, age, disease stage, etc. Acetaminophen and antihistamine were the only pretreatment medications permitted.

A weighted disease burden assessment tool, which included skin lesions, lymph nodes, and blood involvement, was used to determine response to therapy, and all responses were reviewed by an independent outside panel.

Quality of life (QOL) was assessed according to FACT-G, a validated quality-of-life assessment tool composed of five subscores of well-being. QOL was determined at baseline and at the completion of each course of therapy.

Overall, 30% of patients achieved a complete response to DAB_389IL-2 (23% on the 9 µg arm and 35% in the 18 µg arm). Complete response with no evidence of clinical disease for more than 6 weeks, as confirmed by biopsy, was seen in three patients. Four patients had a complete response not confirmed by biopsy, and 14 patients achieved a partial response.

There was no significant difference in overall response between the two arms, but there was a trend toward greater benefit with the 18 µg arm in late-stage CTCL patients.

The responders had a significant improvement in QOL scores, as well as in other secondary endpoints such as pruritus and global skin scores. Improvements were reported in functional, emotional, and social/family well-being. Quality of life was maintained in all patients, including nonresponders, after treatment.

Adverse Events

The main adverse events, all reversible, were fever, chills, nausea, and tumor pain. A flu-like syndrome was a delayed response. Dr. Duvic feels the most significant adverse event was capillary leak, which occurred in 10% of patients 10 days after treatment. Yet, it was reversible, she said.

“This is an exciting new therapy for this disease,” Dr. Duvic said. She thinks the DAB₃₈₉IL-2 regimen could be used as first-line treatment of tumor stage IIB CTCL. It has also shown activity in other lym-phomas and psoriasis.