Recombinant human granulocyte-macrophage colony-stimulating factor in combination with standard induction chemotherapy in de novo acute myeloid leukemia

Abstract

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.

Hematopoietic growth factors in cancer treatment

“…Recruitment could then be demonstrated in vivo after a 24-to 48-h infusion of GM-CSF prior to chemotherapy and appeared as a shift of leukemic blasts from Go to higher RNA and DNA content corresponding to the GI and S phases and also by an increase in S phase cells incorporating BrdU which was found in the majority of patients [33].…”

Practical aspects of cytokine therapy

“…GM-CSF and IL-3 were shown to stimulate the cytotoxicity of cytosine-arabinoside in vitro [74-761, and this concept was employed in several studies with the application of GM-CSF in patients with AML. Myeloblasts from AML patients are able to express surface receptors for a variety of HGFs [77], and treatment with GM-CSF before chemotherapy has been demonstrated to increase the number of cells in cell cycle, particularly in S phase [78,79], where they are thought to be most vulnerable to chemotherapy. Future randomized clinical trials will have to show whether this approach can influence outcome and survival of patients and whether it is clinically relevant for further malignant disorders.…”

Treatment of de novo acute myelogenous leukemia with recombinant granulocyte macrophage-colony-stimulating factor in combination with standard induction chemotherapy: Effect of granulocyte macrophage-colony-stimulating factor on white blood cell counts

“…Twenty patients suffering from de novo AML entered the study after giving written informed consent [7,8]. Diagnoses were established according to FAB criteria.…”

“…The treatment protocol was recently described in detail 181. In brief, rhGM-CSF was administered by continuous iv infusion (daily dose of 250 Kgim'), 48 or 24 hr prior to chemotherapy ("prephase") [7,8]. GM-CSF was administered until the neutrophil count (segmented and banded) was >500/mm3 (after chemotherapy-induced aplasia) and was then changed to subcutaneous application (125 Fgim' twice daily) for the following 3 days (patients 1-6).…”

“…In previous studies, recombinant GM-CSF has also been shown to recruit acute myeloid leukemia (AML) blast cells in vitro to become more sensitive to cell cycle-specific cytotoxic drugs [4-61. Recently, we were able to demonstrate in vivo recruitment of quiescent leukemic cells into the cell cycle using GM-CSF in combination with standard induction chemotherapy in AML patients [7,8]. Here we report on the clinical update of our regimen and focus on the effects of rhGM-CSF on white blood cell (WBC) counts during the initial 24 hr of the "prephase.…”