High Complete Remission Rate in Chemotherapy-Refractory Classic or Variant Hairy Cell Leukemia Induced by the Anti-CD22 Recombinant Immunotoxin RFB4(dsFv)-PE38 (BL22)

RFB4(dsFv)-PE38 (BL22) is a recombinant disulfide-stabilizedimmunotoxin composed of the variable domains (VH and VL) of the anti-CD22monoclonal antibody RFB4 attached by a disulfide bond and with VH fused totruncated Pseudomonas exotoxin. A total of 31 patients withchemotherapy-refractory hairy cell leukemia (HCL), chronic lymphocytic leukemia(CLL), or non-Hodgkin’s lymphoma have received 99 cycles of BL22 at 3 to 50µg/kg IV every other day for 3 doses (qod × 3).

The most common toxicities were hypoalbuminemia, third-spacingof fluid without pulmonary edema, nausea, transaminase elevations, and myalgias.Toxicity was prevented by anti-inflammatory agents and hydration. The 50 µg/kgqod × 3 level was considered dose limiting because one patient developedreversible hemolytic uremic syndrome (HUS) and most other patients had grade 1creatinine 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 10patients were well tolerated. Only 1 out of 31 patients made neutralizingantibodies after 1 cycle, and this patient had preexisting neutralizingantibodies.

Out of 11 purine analog-refractory HCL patients who areevaluable for response, 10 patients achieved complete remission (91% CR) and 1patient 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. Completeremissions were induced after one cycle in 5 of the patients, and 5 required twoto nine cycles to achieve CR. Of the 10 in CR, minimal residual disease by flowcytometry was eliminated in the blood in 10 and in the marrow in 3. Completeremissions were most rapid in patients with mono- or oligoclonal elevations incytotoxic T cells, which often increased with repeated cycles. No patients in CRhave relapsed after up to 1 year of follow-up, based on restaging including bonemarrow biopsy.

CONCLUSION: BL22 showed clinically useful effects in CLL withreductions 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 sincepurine analogs that is capable of inducing CR in the majority of patients withHCL, and is the only agent that can induce CR in most patients withchemotherapy-refractory or variant HCL. Its sparing of T cells may also allowimproved clearing of minimal residual disease.

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