Recombinant human granulocyte-macrophage colony-stimulating factor in combination with standard induction chemotherapy in de novo acute myeloid leukemia.
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.
Bettelheim
P
P
First Medicine Department, University of Vienna, Austria.
Valent
P
P
Andreeff
M
M
Tafuri
A
A
Haimi
J
J
Gorischek
C
C
Muhm
M
M
Sillaber
C
C
Haas
O
O
Vieder
L
L
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001853:Bone Marrow / Q000473:pathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle; D003561:Cytarabine / Q000008:administration & dosage; D004247:DNA / Q000096:biosynthesis; D003630:Daunorubicin / Q000008:administration & dosage; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D006410:Hematopoiesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use
D011994:Recombinant Proteins; D003561:Cytarabine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA; D001973:Bromodeoxyuridine; D003630:Daunorubicin