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Effective immunochemotherapy of CALLA+C mu+ human pre-B acute lymphoblastic
leukemia in mice with severe combined immunodeficiency using B43
(anti-CD19) pokeweed antiviral protein immunotoxin plus cyclophosphamide
FM Uckun, LM Chelstrom, D Finnegan, L Tuel-Ahlgren, C Manivel, JD Irvin, DE Myers and R Gunther
Department of Therapeutic Radiology-Radiation Oncology, University of
Minnesota Health Sciences Center, Minneapolis 55455.
A highly aggressive human CALLA+C mu+ 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 10(6) 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 10(6) leukemia cells.
While neither 15 micrograms 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 10(6) NALM-6- UM1 pre-B ALL cells, the probability of
EFS at 6 months was 50% +/- 16% for SCID mice treated with 15 micrograms
B43-PAP plus 1 mg CPA (median survival, greater than 180 days) (P less than
.0001). The probability of long-term EFS was only 14% +/- 7% for mice
treated with 30 micrograms B43-PAP and 0% +/- 0% for mice treated with 1 mg
CPA, but 40% +/- 16% for mice treated with 30 micrograms B43-PAP plus 1 mg
CPA (P less than .0001). Similarly, the probability of EFS at 6 months was
40% +/- 16% for mice treated with 2 mg CPA alone, 70% +/- 15% for mice
treated with 2 mg CPA plus 15 micrograms B43-PAP, and 70% +/- 15% for mice
treated with 2 mg CPA plus 30 micrograms B43-PAP. Ten SCID mice in the
B43-PAP plus CPA combined immunochemotherapy arms surviving long term after
the inoculation of 5 x 10(6) NALM-6-UM1 pre-B ALL cells were electively
killed at 174 to 181 days to assess their leukemia burden. We found no
evidence of leukemia in any of the bone marrow specimens by two-color
immunofluorescence and multiparameter flow cytometry.(ABSTRACT TRUNCATED AT
400 WORDS)
Volume 79,
Issue 12,
pp. 3116-3129,
06/15/1992
Copyright © 1992 by The American Society of Hematology
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