Hairy Cell Leukemia Responds to New Compound, BL22

NEW ORLEANS—A protein-based compound called BL22 produced complete remissions in patients with hairy cell leukemia resistant to standard therapy with purine analogs. Results of the phase I trial were reported at the 92^nd Annual Meeting of the American Association for Cancer Research (AACR).

Robert J. Kreitman, MD, chief, Clinical Immunology Section, Laboratory of Molecular Biology, National Cancer Institute, reported that 13 of 16 patients with hairy cell leukemia responded to BL22, and 11 achieved a complete remission, most of them long-lasting. The agent was tested in about 30 patients with various chemotherapy-resistant B-cell malignancies.

About 2% of leukemias are hairy cell leukemia, with about 600 new cases diagnosed annually in the United States. Effective chemotherapy keeps many patients in remission for years; however, about 25% become resistant, highlighting the need for new treatments.

"With long-term follow-up, we see that after 8 years or so patients are still not cured with traditional agents. Patients do not stop relapsing over time," Dr. Kreitman said at a press conference held at the AACR meeting.

BL22 is a protein created by the fusion of two major components: a fragment of a monoclonal antibody that binds to the CD22 antigen receptor and a fragment of an exotoxin manufactured by Pseudomonasaeruginosa. "Recombinant DNA techniques allow cloning part of the antibody and part of the toxin to make a smaller recombinant immunotoxin that gets into the tumor faster and reduces toxicity," Dr. Kreitman said.

The drug is one of several new recombinant immunotoxins that have been developed by Ira Pastan, MD, chief of the NCI’s Laboratory of Molecular Biology; David Fitzgerald, PhD, chief of the Biotherapy Section at the Laboratory of Molecular Biology; Dr. Kreitman, and their colleagues.

The three hairy cell leukemia patients who did not respond to BL22 received either low doses of the agent or developed neutralizing antibodies against it, Dr. Kreitman said. Of the 11 patients who completed adequate treatment (one to nine 3-week cycles of BL22, mostly at the higher doses), all achieved a complete remission.

Among the patients in complete remission, no relapses have occurred after up to 20 months of follow-up (median, 11 months). Minimal residual disease as assessed by bone marrow immunohistochemistry was positive in only one of these patients, he said.

T-Cell Expansion

Of the 11 patients in complete remission, nine developed expansions of cytotoxic T cells, assessed by flow cytometry as abnormally high levels of various T lymphocytes. In seven of these nine cases, PCR studies confirmed monoclonal or oligoclonal T-cell expansion.

Of the nine patients with cytotoxic T-cell elevations, three had pre-existing elevations of cytotoxic T cells that increased further with BL22. In two of these three, complete remissions were induced with only one cycle of high-dose BL22 or two cycles of lower-dose BL22.

The researchers concluded that BL22 can induce remissions in most patients with purine analog-resistant hairy cell leukemia. The B-cell specificity of the agent and the sparing of T cells may permit a natural immune response to hairy cell leukemia that is otherwise blunted by disease burden or purine analogs.

"BL22 is the first treatment in 10 years yielding complete remissions in the majority of hairy cell leukemia patients, and is the only agent giving complete remissions in most patients in whom chemotherapy is not effective," Dr. Kreitman stated. "Furthermore, patients do not become resistant to BL22. You can retreat them over and over again."

He added that the agent can induce complete remissions in both patients who are not responding to initial therapy or who become resistant.

Dose-Limiting Toxicity

Dose-limiting toxicity included a completely reversible hemolytic uremic syndrome, observed during cycle 2 in two patients. Taking the drug with large quantities of fluid may make the drug safer to administer, he said.

Dr. Kreitman said that the phase I trial has been extended to include more patients, and a phase II multicenter clinical trial is planned. Trials of BL22 are also planned in patients with chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphoma, and pediatric leukemias.

A license to manufacture BL22 has been issued to AlbaPharm, Inc. (Rockville, Maryland).