Cytarabine, Daunorubicin and Etoposide (ADE) Chemotherapy in Acute Myeloid Leukemia (AML) Patients ≥60 Years (CALGB 9720).
Authors: Baer Maria R. , George Stephen L. , Sanford Ben L. , Bothun Sandra M. , Mrozek Krzysztof , O’Loughlin Kieran L. , Kolitz Jonathan E. , Moore Joseph O. , Stone Richard M. , Powell Bayard L. , Caligiuri Michael A. , Bloomfield Clara D. , Larson Richard A. 
Published: October 2019

Abstract
CALGB 9720 was a phase 3 trial evaluating the multidrug resistance modulator PSC-833 (Valspodar) in induction and consolidation, and subcutaneous interleukin-2 (IL-2) maintenance therapy (rx) in older AML patients (pts). The PSC-833-containing arm was closed after randomization of 120 pts due to excessive toxicity (Blood2002;100:1224). All subsequent pts received ADE induction (A 100 mg/m2/d by 7-day continuous intravenous infusion, with D 60 mg/m2 and E 100 mg/m2 each daily for 3 days), a second induction if needed (same drugs and doses for 5, 2 and 2 days) based on day 14 marrow (BM) cellularity ≥20% and >5% blasts, and one consolidation course (same drugs and doses for 5, 2 and 2 days), and were then randomized to IL-2 or no further rx. We report outcome of ADE rx on this study in 610 pts ≥60 years (yrs; median=70.5 yrs) with de novo AML (n=396; 65%) or secondary AML (S-AML) defined by prior myelodysplastic syndromes or cytotoxic rx (n=168; 28%). Complete remissions (CR) were achieved in 283 (46%) of the 610 pts, 5 (<1%) met CR criteria for <4 weeks, 35 (6%) achieved CR with incomplete count recovery (CRi), and 287 (47%) were non-responders, including 121 with resistant disease and 119 who died during induction. Of 457 pts with day 14 BM data, 344 (75%) did not have BM hypoplasia, but only 99 (29%) received second induction courses. Among 583 pts with information available, 455 (78%) received one course and 128 (22%) two courses, with CR rates of 52% and 35%, respectively. CR rates were 27%, 44% and 51% for pts with complex karyotypes (≥3 abnormalities), rare aberrations (Blood2006;108:63) and neither finding, respectively (p<0.0001); 53% and 36% for de novo and S-AML (p=0.0004); 53%, 42% and 27% for ages 60–69, 70–79 and ≥80 yrs (p=0.0007); and 38% and 54% for pts whose blasts did and did not overexpress P-glycoprotein (Pgp) (p=0.05). In a multivariable logistic regression model adjusted for log(WBC) and sex, predictors of CR success included non-complex/non-rare karyotypes vs. complex (≥3 abnormalities; p<0.0001); de novo vs. S-AML (p=0.0005); and decreasing age (p=0.0008). 253 pts (38%) received consolidation rx, and 157 were randomized to IL-2 (n=81) or no further rx (n=82), with no difference in outcome (Blood2006;108:129a). Both disease-free survival (DFS) and overall survival (OS) were short, with medians of 6.8 and 7.3 months. In univariable analyses, DFS was worse for complex karyotypes (≥5 abnormalities; p<0.0001) and for S-AML (p=0.0023). In a multivariable analysis adjusted for sex and age, DFS was worse for complex (≥5 abnormalities) karyotypes (p<0.0001), increasing WBC (p=0.0005) and S-AML (p=0.008). In univariable analyses, OS was worst for complex karyotypes (≥5 abnormalities; p<0.0001); S-AML (p<0.0001); increasing age (p=0.0004); and Pgp (p=0.04). In a multivariable analysis adjusted for sex, OS was worse for complex karyotypes (≥5 abnormalities; p<0.0001); increasing WBC (p=0.0001); S-AML (p=0.0016); and increasing age (p=0.0003). Intensification of standard 7+3 AD rx by dose-escalation of D and addition of E did not improve outcomes compared with historical 7 + 3 trials, nor alter the influence of previously established adverse prognostic factors in older AML pts.