Responses in Refractory Hairy Cell Leukemia to a Recombinant Immunotoxin

Abstract

We report major responses in 4 of 4 patients with hairy cell leukemia (HCL) who have recently been treated on a phase I trial with the recombinant immunotoxin LMB-2. The immunotoxin, designed to target CD25+ malignancies, is composed of the Fv portion of the anti-Tac (anti-CD25) antibody, fused to a 38-kD truncated form of Pseudomonas exotoxin A, and has previously been called anti-Tac(Fv)-PE38. All 4 HCL patients were resistant to standard and salvage therapies for HCL, including 2-chlorodeoxyadenosine (CdA) and interferon , and all patients responded to LMB-2 after a single cycle. One patient treated with 2 cycles had a complete remission (CR), with regression of HCL cells from the blood and marrow and resolution of splenomegaly and pancytopenia. As is typical for patients in CR after treatment with CdA, minimal residual disease was detectable by flow cytometry of the bone marrow aspirate. This patient has not relapsed after 11 months. Three other patients had 98% to 99.8% reductions in malignant circulating cells. These results represent a proof of principal that targeted therapy with recombinant Fv-containing proteins can be clinically useful. LMB-2 may be an effective new therapy for patients with chemotherapy-resistant CD25+HCL.

CD52 expression in hairy cell leukemia

“…The chimeric anti-CD20 antibody, rituximab, has been shown to induce complete remission in a significant portion of patients with relapsed and newly diagnosed HCL [9]. Recombinant immunotoxin conjugated antibodies directed against CD25 and CD22 have been shown to be effective in patients with HCL with chemotherapy-resistant disease [7,8]. The demonstration of CD52 on HCL cells offers an additional therapeutic target for treatment of refractory HCL.…”

“…Still, cases of HCL leukemia refractory to standard therapy occur, and effective alternatives are limited. Antibody therapy directed against antigens expressed on the neoplastic hairy cells might offer a salvage strategy for patients who have failed purine nucleoside analogues [6][7][8][9].…”

Novel conjugates of single‐chain Fv antibody fragments specific for stem cell antigen CD123 mediate potent death of acute myeloid leukaemia cells

“…Although the immunogenicity of immunotoxins containing bacterial toxins can be reduced by the methods described above, and although their systemic toxicities can be controlled by clinical management (Kreitman et al, 1999), these immunotoxins have not yet been well accepted by the clinical community. This may change in the future, if two of the advanced agents using bacterial toxins, a CD22-scFv-ETA protein (Kreitman et al, 2001) and the fusion of a truncated diphtheria toxin and IL-3 (Testa et al, 2005), which are currently in clinical testing, should receive drug approval.…”

Anti-HIV-1 immunotoxin 3B3(Fv)-PE38: enhanced potency against clinical isolates in human PBMCs and macrophages, and negligible hepatotoxicity in macaques

“…Immunotoxins have great potential for selective cell depletion in a variety of clinical settings including cancer, graft vs. host disease, autoimmune disorders, allograft rejection, and viral infections. Such bifunctional proteins have received the greatest attention for rational design of anti-cancer therapeutics [18 -20]; indeed recent Phase I clinical trials have reported major responses against several hematologic malignancies [37][38][39][40][41], including many complete remissions in cases of chemotherapy-resistant hairy cell leukemia. Moreover, a conceptually related agent (Mylotarg) consisting of a cytoxic antibiotic chemically coupled to a recombinant monoclonal antibody has been approved for treatment of relapsing acute myelocytic leukemia in individuals over 60 years of age who are not considered candidates for cytotoxic chemotherapy [42].…”