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Anti-CD33 monoclonal antibody and etoposide/cytosine arabinoside
combinations for the ex vivo purification of bone marrow in acute
nonlymphocytic leukemia
PJ Stiff, WC Schulz, M Bishop and L Marks
Department of Medicine, Loyola University Stritch School of Medicine,
Maywood, IL 60153.
Pharmacologic and immunologic methods of ex-vivo bone marrow (BM) purging
for acute nonlymphocytic leukemia (ANLL) were combined to augment the
effect of either method alone. Etoposide (VP16; 20 to 30 micrograms/mL)
with or without cytosine arabinoside (Ara C; 10 mg/mL) was used in tandem
with the anti-CD33 monoclonal antibody (MoAb), MY9, chosen because CD33 is
found on the stem cell pool in the majority of patients with ANLL. The
agents were tested singly or sequentially, with a 1-hour incubation of the
drugs preceding complement-mediated lysis using MY9. VP16 combined with Ara
C killed up to 3.9 +/- 0.3 and 5.11 +/- 0.4 logs of the human ANLL cell
lines HL60 and K562 at drug concentrations that killed only 1.2 +/- 0.1
logs of normal committed granulocyte/macrophage stem cells (CFU-GM). Adding
a single exposure of the MY9 and complement (C') to the drug-treated cells,
greater than 5.4 logs of HL60 were killed. Similar to other pharmacologic
agents, no differential kill for clonagenic leukemic cells (colony-forming
unit- leukemia; CFU-L) from patients with ANLL was seen for drug only
treated blasts versus normal CFU-granulocyte-macrophage (CFU-GM), with less
than 1 log CFU-L kill at drug concentrations that spared 1 log of CFU- GM.
Similarly, only 1.1 +/- 0.3 logs of ANLL CFU-L were eliminated using MY9
and C'. However, with the sequential VP16/Ara C----MY9 + C' treatment,
synergy was demonstrated and 2.6 +/- 0.3 logs of CFU-L were eliminated.
Because CD33 is also found on the normal CFU-GM pool, two- stage long-term
BM cultures were performed to determine pluripotent stem cell elimination
by the drug/MoAb purging combination. No difference of CFU-GM or BFU-E
production at 4 to 6 weeks of culture for VP16/Ara C, MY9 + C', or
VP16/AraC----My9 + C' treated cells was seen compared with untreated
controls indicating sparing of early progenitor cells. Sequential ex vivo
treatment of human ANLL CFU-L with VP16/Ara C followed by
complement-mediated lysis using MY9 synergistically kills CFU-L while
sparing early normal hematopoietic progenitor cells, and thus may be a more
effective way to purge BM than either alone.
Volume 77,
Issue 2,
pp. 355-362,
01/15/1991
Copyright © 1991 by The American Society of Hematology
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