Going Beyond 7 + 3 Regimens in the Treatment of Adult Acute Myeloid Leukemia

Current management in acute myeloid leukemia (AML) includes induction chemotherapy followed by several courses of consolidation chemotherapyorallogeneicstem-cell transplantation(SCT).Theexpression 7 3 stands for a combination of intravenous chemotherapy that includes 7 days of cytarabine (AraC; 100 mg/m per day by continuous infusion) and 3 days of daunorubicin (DNR; 45 mg/m per day, given on days 1, 2, and 3). A series of pre-1985 studies by the Cancer and Leukemia Group B established 7 3 as the standard induction regimen for newly diagnosed AML. In addition, a DNR dose of 45 mg/m per day (DNR 45) was superior to DNR 30 mg/m per day (DNR 30) in the 7 3 regimen, with respect to achievement of complete remission (CR) in patients younger than age 60 years. Increasing the dose of AraC to 200 mg/m per day, extending its infusion period to 10 days (10 3), or the addition of oral thioguanine 100 mg/m twice per day on days 1 to 7 (7 3 7) did not additionally improve the results. CR rates for 7 3 ranged from 53% to 58%, were higher in younger patients (59% to 72% v 31% to 45% for patients older than age 60 years), and were maintained over the long term in less than 15% of patients. The value of postremission therapy was also recognized early, underscoring the fact that achievement of CR with current chemotherapy is not enough to cure AML. Through the years, many studies have been conducted with the intent to improve on 7 3. Substituting other anthracyclines for DNR on days 1, 2, and 3 suggested that some anthracyclines might be better than others. Mitoxantrone 8 to 12 mg/m per day compared with DNR 30 to 50 gave higher CR rates in some studies but not in others. In one of these studies, DNR 50, mitoxantrone 12 mg/m per day, and idarubicin (IDA) 10 mg/m per day displayed similar activity. However, the preponderance of current evidence favors IDA 12 to 13 mg/m per day compared with DNR 45 to 50 in terms of both CR rates (70% to 80% v 58% to 59%) and possibly survival. More recently, on the basis of earlier indications, doubling the dose of DNR to 90 mg/m per day for 3 days (DNR 90) was shown to induce significantly higher CR rates, compared with DNR 45, in select subsets of young (age 60 years or younger; 71% v 57%) and older (age 60 years and older; 64% v 54%) patients. These studies also demonstrated better overall survival for a subgroup of younger patients (younger than age 50 years or age 60 to 65 years) who were treated with DNR 90. A more recent study confirmed the results by Fernandez et al, in that the advantage of DNR 90 compared with DNR 45 was restricted to patients with an intermediate-risk karyotype and was less apparent in those with an unfavorable karyotype or high-risk molecular profile. The study by Lowenberg et al suggested that DNR 90 also benefitted patients with a favorable karyotype. Amsacrine and gemtuzumab ozogamicin (GO) have also been compared to DNR, in the context of a 7 3 strategy, with an advantage seen with the former but not the latter. In a nonrandomized comparison, both fludarabine and topotecan were shown to be inferior to DNR as induction partners to AraC. Similarly, no additional benefit was gained by adding a third drug to 7 3, including etoposide (75 mg/m per day on days 1 through 7), myeloid growth factors, P-glycoprotein modulator (PSC833), or GO, although the addition of GO might have benefitted patients with a favorable karyotype. Dose-intensification of 7 3 has also been attempted for AraC; a dose increase to 4 g/m per day or 6 g/m per day did not result in improved CR rates but might have prolonged remission duration without affecting overall survival. Highdose AraC has also been incorporated as part of a double induction strategystartingonday21withoutaffectingCRoroverall survival. The use of high-dose AraC and granulocyte colony-stimulating factor (GCSF) in combination with fludarabine was not superior to high-dose AraC plus G-CSF, but the possibility was recently noted that AraC plus G-CSF in combination with fludarabine plus IDA might perform better. In the article that accompanies this editorial, Holowiecki et al report on a large (n 652) multicenter trial of young patients (age 60 years or younger) with AML (excluding acute promyelocytic leukemia) who were randomly assigned to receive 7 3 alone (DA), or DA with a 3-hour infusion of cladribine (5 mg/m per day on days 1 through 5; DAC), or DA with a 30-minute infusion of fludarabine (25 mg/m per day on days 1 through 5). The corresponding CR rates were 56%, 68%, and 59%, in favor of DAC (P .01). Consolidation chemotherapy included high-dose AraC followed by SCT or 2-year maintenance chemotherapy, determined on the basis of risk of relapse. Three-year overall survival rates were 45% for DAC, 33% for DA (P .02), and 35% for DA plus fludarabine; leukemia-free survival and toxicity were not significantly different between the three arms. The outcome advantage for DAC was also apparent in patients with an unfavorable karyotype and possibly for those with a favorable karyotype. The results from the current Polish study confirm the authors’ initial observations comparing DAC to DA in the treatment of newly diagnosed AML and are also consistent with recent information on the anti-AML therapeutic value of clofarabine, a structurally JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 20 JULY 1