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Recombinant human granulocyte-macrophage colony-stimulating factor in
combination with standard induction chemotherapy in de novo acute myeloid
leukemia
P Bettelheim, P Valent, M Andreeff, A Tafuri, J Haimi, C Gorischek, M Muhm, C Sillaber, O Haas and L Vieder
First Medicine Department, University of Vienna, Austria.
Based on in vitro data suggesting that recombinant human granulocyte-
macrophage colony-stimulating factor (rhGM-CSF) is capable of stimulating
acute myeloid leukemia (AML) blast cells to become more sensitive to
cell-cycle-specific drugs we conducted a phase I/II study in de novo AML
patients (pts). rhGM-CSF (250 micrograms/m2/d, continuous intravenous
infusion) was administered in 18 pts suffering from de novo AML in
combination with standard induction chemotherapy (3 + 7 = daunorubicin 45
mg/m2 days 1 through 3, cytosine-arabinoside [Ara- C] 200 mg/m2 continuous
infusion days 1 through 7). GM-CSF was started 48 or 24 hours before
chemotherapy (prephase) in 14 pts. In four pts with high white blood cell
counts (WBC) rhGM-CSF was started after chemotherapy-induced cell reduction
(WBC less than 30,000/mm3). During prephase GM-CSF induced an increase in
neutrophil and blast cell counts in 13 of 14 and 10 of 14 pts,
respectively. In vivo recruitment of leukemic cells into drug-sensitive
phases of the cell cycle could be demonstrated by multiparameter cell-cycle
analyses in peripheral blood (n = 7) and bone marrow (n = 4) specimens. On
day 14, complete aplasia was evident in 17 of 18 pts. GM-CSF was
administered until recovery from chemotherapy-induced myelosuppression
(absolute neutrophil counts, [ANC] greater than 500/mm3). Fifteen pts (83%)
achieved complete remission, 12 did so with one cycle. A shorter duration
of neutropenia was evident in these pts compared with historical controls
(n = 39), (ANC greater than 500/mm3, day 22.5 +/- 3.4 v 25.2 +/- 3.7, P
less than .05). Three pts achieved complete remission after a second cycle
(same combination of rhGM-CSF and 3 + 7). Two pts died during bone marrow
aplasia because of invasive pulmonary aspergillosis. Clinical side effects
possibly related to GM-CSF, mainly fever, diarrhea, and weight gain were
mild and tolerable (World Health Organization toxicity grade less than or
equal to 2). Together, rhGM-CSF recruits kinetically quiescient AML cells
in vivo to enter drug-sensitive phases of the cell cycle and promotes early
myeloid recovery from aplasia after exposure to standard induction
chemotherapy for AML.
Volume 77,
Issue 4,
pp. 700-711,
02/15/1991
Copyright © 1991 by The American Society of Hematology
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