Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS)

• Type of Material: Article
• Authors: Hagop M Kantarjian, University of Texas MD Anderson Cancer Center; Kebede H Begna, Mayo Clinic, Rochester; Jessica K Altman, Northwestern University; Stuart L Goldberg, Hackensack University; Mikkael A Sekeres, Cleveland Clinic; Stephen Strickland, Vanderbilt-Ingram Cancer Center; Martha Arellano, Emory University; David F Claxton, Penn State Milton S. Hershey Medical Center; Maria R Baer, University of Maryland Greenebaum Comprehensive Cancer Center; Marc Gautier, Dartmouth-Hitchcock Medical Center; Ellin Berman, Memorial Sloan Kettering Cancer Center; Karen Seiter, New York Medical College; Scott R Solomon, Northside Hospital Cancer Institute; Gary J Schiller, University of California Los Angeles; Selina M Luger, University of Pennsylvania; Aleksandra Butrym, Wroclaw Medical University; Gianluca Gaidano, AOU Maggiore della Carita; Xavier Thomas, Centre Hospitalier Sud, Lyon, France; Pau Montesinos, Hospital Universitario y Politecnico La Fe, Valencia, Spain; David Rizzieri, Duke University; Donald Quick, Joe Arrington Cancer Center, Lubbock; Parameswaran Venugopal, Rush University; Rakesh Gaur, St. Luke’s Cancer Institute; Lori J Maness, University of Nebraska Medical Center; Tapan M Kadia, University of Texas MD Anderson Cancer Center; Farhad Ravandi, University of Texas MD Anderson Cancer Center; Marc E Buyse, International Drug Development Institute; Judy H Chiao, Cyclacel Ltd
• Language: English
• Date: 2021-08-23
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 American Cancer Society
• Final Published Version (URL): http://dx.doi.org/10.1002/cncr.33828
• Title of Journal or Parent Work: CANCER
• Volume: 127
• Issue: 23
• Start Page: 4421
• End Page: 4431
• Grant/Funding Information: Cyclacel Limited is the sponsor of this study
• Keywords: DECITABINE; Life Sciences & Biomedicine; MULTICENTER; acute myeloid leukemia (AML); OLDER PATIENTS; therapy; STRAND BREAKS; decitabine; Science & Technology; Oncology; SUPPORTIVE CARE; RESPONSE CRITERIA; INTERNATIONAL WORKING GROUP; sapacitabine; THERAPY; hypomethylation; TRIALS; MECHANISM

Abstract

Background: Acute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low-intensity therapy, to elderly patients with newly diagnosed AML. Methods: This randomized, open-label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1-hour intravenous infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1-hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (<10 × 109/L and ≥10 × 109/L), and bone marrow blast percentage (≥50% vs <50%). The primary end point was overall survival (OS). Secondary end points were the rates of complete remission (CR), CR with incomplete platelet count recovery, partial remission, hematologic improvement, and stable disease along with the corresponding durations, transfusion requirements, number of hospitalized days, and 1-year survival. The trial is registered at ClinicalTrials.gov (NCT01303796). Results: Between October 2011 and December 2014, 482 patients were enrolled and randomized to receive decitabine administered in alternating cycles with sapacitabine (study arm, n = 241) or decitabine monotherapy (control arm, n = 241). The median OS was 5.9 months on the study arm versus 5.7 months on the control arm (P =.8902). The CR rate was 16.6% on the study arm and 10.8% on the control arm (P =.1468). In patients with white blood cell counts <10 × 109/L (n = 321), the median OS was higher on the study arm versus the control arm (8.0 vs 5.8 months; P =.145), as was the CR rate (21.5% vs 8.6%; P =.0017). Conclusions: The regimen of decitabine administered in alternating cycles with sapacitabine was active but did not significantly improve OS compared with decitabine monotherapy. Subgroup analyses suggest that patients with baseline white blood cell counts <10 × 109/L might benefit from decitabine alternating with sapacitabine, with an improved CR rate and the convenience of an oral drug. These findings should be prospectively confirmed.