RFB4(dsFv)-PE38 (BL22) is a recombinant disulfide-stabilized immunotoxin composed of the variable domains (VH and VL) of the anti-CD22 monoclonal antibody RFB4 attached by a disulfide bond and with VH fused to truncated Pseudomonas exotoxin. A total of 31 patients with chemotherapy-refractory hairy cell leukemia (HCL), chronic lymphocytic leukemia (CLL), or non-Hodgkin’s lymphoma have received 99 cycles of BL22 at 3 to 50 µg/kg IV every other day for 3 doses (qod × 3).
The most common toxicities were hypoalbuminemia, third-spacing of fluid without pulmonary edema, nausea, transaminase elevations, and myalgias. Toxicity was prevented by anti-inflammatory agents and hydration. The 50 µg/kg qod × 3 level was considered dose limiting because one patient developed reversible hemolytic uremic syndrome (HUS) and most other patients had grade 1 creatinine elevation or proteinuria, which was considered a risk factor for HUS. The maximum tolerated dose was 40 µg/kg qod × 3, where all 18 cycles in 10 patients were well tolerated. Only 1 out of 31 patients made neutralizing antibodies after 1 cycle, and this patient had preexisting neutralizing antibodies.
Out of 11 purine analog-refractory HCL patients who are evaluable for response, 10 patients achieved complete remission (91% CR) and 1 patient had a partial response (9% PR). All 3 patients with variant HCL (HCLv) had never been in CR with previous chemotherapy but had CR to BL22. Complete remissions were induced after one cycle in 5 of the patients, and 5 required two to nine cycles to achieve CR. Of the 10 in CR, minimal residual disease by flow cytometry was eliminated in the blood in 10 and in the marrow in 3. Complete remissions were most rapid in patients with mono- or oligoclonal elevations in cytotoxic T cells, which often increased with repeated cycles. No patients in CR have relapsed after up to 1 year of follow-up, based on restaging including bone marrow biopsy.
CONCLUSION: BL22 showed clinically useful effects in CLL with reductions of circulating CLL cells (> 99.9% in 1 patient) and lymph nodes, although CRs have not yet been observed. Thus BL22 is the first agent since purine analogs that is capable of inducing CR in the majority of patients with HCL, and is the only agent that can induce CR in most patients with chemotherapy-refractory or variant HCL. Its sparing of T cells may also allow improved clearing of minimal residual disease.