Phase II trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with hairy cell leukemia

Abstract

Purpose: To conduct a phase II trial in chemoresistant hairy cell leukemia (HCL) with BL22, a recombinant anti-CD22 immunotoxin which showed phase I activity in HCL.

Patients and methods: Eligible patients had relapsed/refractory HCL and needed treatment based on blood counts. Patients were stratified into three groups: response to cladribine less than 1 year, those with a response lasting 1 to 4 years, or no response and uncontrolled infection. Patients received BL22 40 microg/kg every other day for three doses on cycle 1. Those achieving hematologic remission (HR), defined as neutrophils > or = 1,500/mm(3), hemoglobin > or = 11 g/dL, and platelets > or = 100,000/mm(3), were observed. Patients without HR were re-treated at 30 microg/kg every other day for three doses every 4 weeks beginning at least 8 weeks after cycle 1.

Results: Thirty-six patients were enrolled including 26, nine, and one in groups 1 to 3. The response after one cycle (CR, 25%; PR, 25%) improved when 56% were re-treated (CR, 47%; PR, 25%). CR rate was similar in groups 1 and 2 (P = .7). Twenty-two with baseline spleen height lower than 200 mm had higher CR (64% v 21%; P = .019) and OR rates (95% v 36%; P = .0002) compared to 14 with spleens either absent or higher than 200 mm. The only serious toxicity was reversible grade 3 hemolytic uremic syndrome, not requiring plasmapheresis, in two patients (6%). High neutralizing antibodies were observed in four patients (11%) and prevented re-treatment.

Conclusion: BL22 activity in HCL is confirmed. Best responses to BL22 after cladribine failure are achieved before the patients develop massive splenomegaly or undergo splenectomy.

Fig 1.

CONSORT flow diagram. Disposition of study participants. After cycle 1, patients with complete (CR) or hematologic remission (HR) were observed, and those with partial remission (PR) or stable disease (SD) were retreated if eligible. Patients ineligible for retreatment after PR or SD had dose-limiting toxicities, infection, or immunogenicity. QOD, every other day; PD, progressive disease.

Fig 2.

Patterns of response. (A) Complete response (CR) in patient BH03 requiring five cycles of BL22 before achieving negative marrow, then two consolidation cycles. (B) CR in patient BH11 after one cycle of BL22. Neither patient has relapsed after 36 to 46 months of follow-up. C, cycle; ANC, absolute neutrophil count; HGB, hemoglobin; HCL, hairy cell leukemia.

Fig 3.

Durability of response. Left axis show % of 36 patients remaining in (A) hematologic remission (HR), (B) complete remission (CR), and (C) CR without (W/O) MRD. Red bars indicate follow-up of nonrelapsing patients. Right axes indicate % of the 22, 17, and 14 patients originally achieving HR, CR, and CR without minimal residual disease, respectively, who remain relapse free.

Fig 4.

Toxicity of BL22 on cycle 1 (left) and with retreatment (right). For each graph, grade 1 to 2 events occurring only once are not shown. LEA, lower extremity arterial; GGT, gamma glutamyl transferase; EFFU, effusion; ABD, abdominal; HEAD&N, head and neck; HUS, hemolytic uremic syndrome; ALK PHOS; alkaline phosphatase; SOB, shortness of breath.

Fig 5.

Pharmacokinetics of BL22. Area under the curves (AUCs) are shown (A, B, E) after cycle 1 or (C, D, F) re-treatment in patients with (A-D) and without (E-F) spleens. Cycles associated with hemolytic uremic syndrome are in red. Correlations did not include BH09 in group 3 (labeled gold in E) who required blood products possibly containing antibodies during BL22 infusion. HCL, hairy cell leukemia.