BETHESDA"BL22 is the first agent since purine analogs
capable of inducing complete remission in the majority of patients with hairy
cell leukemia, and the only agent that can induce complete remission in most
patients with chemotherapy-refractory or variant HCL," according to Robert
J. Kreitman, MD. "Its sparing of T cells," he continued, "may
also allow improved clearing of minimal residual disease."
Dr. Kreitman, who is chief of the Clinical Immunotherapy
Section at the National Cancer Institute’s Laboratory of Molecular Biology in
Bethesda, described results of a phase-I trial of BL22 (RFB4(dsFv)-PE38), a
recombinant disulfide-stabilized immunotoxin composed of the variable domains
of the anti-CD22 monoclonal antibody RFB4 attached together by a disulfide bond
and fused to truncated Pseudomonas exotoxin. (See Figure 1.) Dr. Kreitman said
that the investigators’ goal was to "use the extreme potency of
Pseudomonas exotoxin, which can kill cells with only one molecule in the
This phase-I study enrolled 31 patients with
chemotherapy-refractory hairy cell leukemia (HCL, n = 16), chronic lymphocytic
leukemia (CLL, n = 11), or non-Hodgkin’s lymphoma (NHL, n = 4) who had CD22
expression on their malignant cells. Each patient received BL22 at 3-50 µg/kg
IV every other day for three doses. Thus far, the investigators have
administered up to 12 cycles of treatment per patient (range, 1-12).
"Only 3 of 31 patients made neutralizing antibodies, which
indicates that this treatment has low immunogenicity and can be given for many
cycles," Dr. Kreitman said.
The most common toxicities were hypoalbuminemia, third-spacing
of fluid without pulmonary edema, nausea, transaminase elevations, and
myalgias. Toxicity was often decreased during re-treatment using
anti-inflammatory agents and hydration. The cytokine release syndrome also seen
with many monoclonal antibody therapies occurred in only one hairy cell
leukemia patient, who had neutralizing antibodies prior to therapy. Dr.
Kreitman said that low immunogenicity might be due to the structure of BL22, a
small molecule that does not include the IgG constant domains.
"Alternately, it might be that these patients are more immunosuppressed
than those with solid tumors and less likely to mount an immune response, or
that BL22 might have some degree of anti-B-cell activity."
Hemolytic Uremic Syndrome
The dose limiting level was 50 µg/kg qod × 3. One patient
developed acute, reversible, renal insufficiency that is now suspected of being
hemolytic uremic syndrome (HUS) and two other patients developed reversible
HUS. Dr. Kreitman said that this problem was not seen in subsequent patients
who had good hydration and no intravenous contrast before BL22. The maximum
tolerated dose was 40 µg/kg qod × 3, where all cycles were well tolerated.
"HUS remains a serious potential toxicity," Dr.
Kreitman said, "but it may be preventable."
Dr. Kreitman reported that BL22 produced responses in 13 of 16
patients11 complete remissions (CR) and 2 partial responses. All were
refractory to purine analog treatment. The 3 nonresponders had either low doses
or preexisting neutralizing antibodies. "Most patients had over 90%
eradication of hairy cells (demonstrated by flow cytometry) within 2 days and
nearly 100% eradication within 1 week of beginning treatment," he said.
"Greater disease burden did not prevent the achievement of CR but
sometimes required additional cycles of treatment."
All three patients with variant HCL (HCLv) had never been in CR
with previous chemotherapy but had CR in response to BL22. Complete responses
were most rapid in patients with mono- or oligoclonal elevations in cytotoxic T
cells, which often increased with repeated cycles. Pancytopenia reversed in
responders and transfusion dependence resolved.
"At a median follow-up of 7 months, there were no relapses
from CR," Dr. Kreitman said. "No other agent comes close to the
activity of BL22 in this poor-prognosis group, and it is the only agent so far
to produce a high CR rate in purine-analog-resistant patients."