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aHiDAC, high-dose cytarabine; Mito, mitoxantrone; IDAC, intermediate-dose cytarabine; E, etoposide; MEC, mitoxantrone, etoposide, cytarabine; GM, granulocyte macrophage colony-stimulating factor; G, granulocyte colony-stimulating factor; D, daunomycin; CSP, cyclosporine; NA, not available.

bKaranes study included patients with primary refractory disease and first relapse.

cList study included patients with primary refractory disease and first relapse (N=177) and patients with AML evolving from MDS (N=49).

aHiDAC, high-dose cytarabine; Mito, mitoxantrone; IDAC, intermediate-dose cytarabine; E, etoposide; MEC, mitoxantrone, etoposide, cytarabine; GM, granulocyte macrophage colony-stimulating factor; G, granulocyte colony-stimulating factor; D, daunomycin; CSP, cyclosporine; NA, not available.

bKaranes study included patients with primary refractory disease and first relapse.

cList study included patients with primary refractory disease and first relapse (N=177) and patients with AML evolving from MDS (N=49).

versus intermediate-dose cytarabine when combined with mitoxantrone.28 They reported a trend toward a higher CR rate (52% vs 44%) and a slightly longer duration of second remission (median of 5 vs 3 months) with the higher dose regimen. However, because of a greater early death rate with the higher dose regimen, no benefit in overall survival was seen.

Several studies have addressed the impact of adding other drugs to high-dose cytarabine. Vogler et al. asked whether there was any benefit from adding etoposide to high-dose cytarabine, and reported that CR rates were similar (40% with cytarabine alone vs 45% with cytarabine and etoposide).29 They also did not see a difference in remission duration in the two arms of the study. Karanes et al. asked whether there was any benefit from adding mitoxantrone to high-dose cytara-bine.30 They reported a significantly higher CR rate with the addition, but no improvement in overall survival.

A third group of studies has attempted to evaluate the impact of the addition of hematopoietic growth factors to chemotherapy for recurrent AML. Thomas et al. asked whether the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to the MEC combination improved outcome. In this study, GM-CSF was given during chemotherapy in an effort to recruit cells into cycle, thereby sensitizing them to GM-chemotherapy. The CR rates in both arms of the study were remarkably high (81% without GM-CSF vs 89% with CSF), but not different from each other.31 The median survival was somewhat better than seen in other studies (8.5 vs 10 months, respectively). Ohno et al. studied the addition of G-CSF to the MEC combination and reported CR rates of 54% with G-CSF versus 42% without G-CSF.32

A final group of studies addressed whether inhibition of the multidrug-resistance pump using cyclosporine might benefit patients. In a randomized trial, List et al. found that adding cyclosporine to a combination of high-dose cytarabine and dauno-mycin led to significantly less treatment failure due to drug resistance, and improved both disease-free survival and overall survival.33 However, a smaller study from the Dutch group, which tested the addition of cyclosporine to the combination of mitox-antrone and etoposide, found that although the CR rate was higher with cyclosporine (53% vs 43%), there was no improvement in overall survival, possible due to inadequate postinduction therapy as a result of the toxicities of the reinduction treat-ment.34

The experience of the Dutch group is typical. All of these aggressive reinduction regimens are accompanied by significant toxicities, including the risks of significant organ damage and the acquisition of infections, which may make further therapy, including HCT, difficult or impossible. Thus, the search for effective, less toxic therapies continues.

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