Effective immunochemotherapy of CALLA+Cμ+ human pre-B acute lymphoblastic leukemia in mice with severe combined immunodeficiency using B43 (anti-CD19) pokeweed antiviral protein immunotoxin plus cyclophosphamide

Abstract

A highly aggressive human CALLA+Cμ+ pre-B acute lymphoblastic leukemia (ALL) cell line (NALM-6-UM1) causes disseminated and invariably fatal leukemia in CB.17 mice with severe combined immunodeficiency (SCID). We used this SCID mouse model of human pre-B ALL to evaluate and compare, in a total of 434 SCID mice, the antileukemic efficacy of B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin and cyclophosphamide (CPA) as individual reagents and as combined immunochemotherapeutic regimens. B43-PAP plus CPA was superior to either the immunotoxin or drug alone, and combined immunochemotherapy markedly improved the event-free survival (EFS) of SCID mice challenged with NALM-6-UM1 pre-B ALL cells. Notably, 90% to 100% of SCID mice challenged with 1 x 106 leukemia cells and then treated with B43-PAP plus CPA combined immunochemotherapy regimens became long-term survivors, a result not achieved with B43-PAP alone or CPA alone. The advantage was particularly evident in mice inoculated with 5 x 106 leukemia cells. While neither 15 μg B43-PAP (median survival, 58 days) nor 1 mg CPA (median survival, 49 days) resulted in long-term EFS of SCID mice challenged with 5 x 106 NALM-6-UM1 pre-B ALL cells, the probability of EFS at 6 months was 50% ± 16% for SCID mice treated with 15 μg B43-PAP plus 1 mg CPA (median survival, >180 days) (P < .0001). The probability of long-term EFS was only 14% ± 7% for mice treated with 30 μg B43-PAP and 0% ± 0% for mice treated with 1 mg CPA, but 40% ± 16% for mice treated with 30 μg B43-PAP plus 1 mg CPA (P