NEW ORLEANSA 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
92nd Annual Meeting of the American Association for Cancer Research
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
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 Pseudomonas aeruginosa.
"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.
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
"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 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
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).