@article{fae0cb0ae83043db91062eceec9afb03,
title = "Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS)",
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.",
keywords = "acute myeloid leukemia (AML), decitabine, hypomethylation, sapacitabine, therapy",
author = "Kantarjian, {Hagop M.} and Begna, {Kebede H.} and Altman, {Jessica K.} and Goldberg, {Stuart L.} and Sekeres, {Mikkael A.} and Strickland, {Stephen A.} and Arellano, {Martha L.} and Claxton, {David F.} and Baer, {Maria R.} and Marc Gautier and Ellin Berman and Karen Seiter and Solomon, {Scott R.} and Schiller, {Gary J.} and Luger, {Selina M.} and Aleksandra Butrym and Gianluca Gaidano and Thomas, {Xavier G.} and Pau Montesinos and Rizzieri, {David A.} and Quick, {Donald P.} and Parameswaran Venugopal and Rakesh Gaur and Maness, {Lori J.} and Kadia, {Tapan M.} and Farhad Ravandi and Buyse, {Marc E.} and Chiao, {Judy H.}",
note = "Funding Information: This work was sponsored by Cyclacel Limited (Dundee, Scotland, United Kingdom). Funding Information: Hagop M. Kantarjian reports research grants from AbbVie, Amgen, Ascentage, Bristol‐Myers Squibb, Daiichi‐Sankyo, Immunogen, Jazz, Novartis, Pfizer, and Sanofi; and honoraria from AbbVie, Actinium (advisory board), Adaptive Biotechnologies, Amgen, Aptitude Health, BioAscend, Daiichi‐Sankyo, Delta Fly, Janssen Global, Novartis, Oxford Biomedical, Pfizer, and Takeda Oncology outside the submitted work. Jessica K. Altman reports unpaid participation on advisory boards for Kura, Daiichi Sankyo Company, and BioSight; and personal fees from participation on advisory boards at Astellas Pharmaceuticals, Syros, AbbVie, Amgen, Theradex, and Agios outside the submitted work. Stephen Strickland reports institutional research funding from Sunesis and honoraria from AbbVie, ArcherDx, Genentech, Incyte, Kura Oncology, Novartis, Pfizer, and Syros outside the submitted work. Martha L. Arellano reports personal fees from Syndax Pharmaceuticals outside the submitted work. David Claxton reports funding to his institution for clinical trials from Novartis Pharmaceuticals, Astex Pharmaceuticals, Daiichi‐Sankyo, and Incyte outside the submitted work. Karen Seiter reports grants from Takeda, Incyte, Chimerix, Sellas, Glycomimetrics, Theradex, Amphivena, Jazz, Millennium Pharmaceuticals, and Roche; honoraria from Jazz, Incyte, Novartis, Astellas, and Celgene; and meeting/travel support from Jazz, Incyte, Novartis, and Celgene outside the submitted work. Gary J. Schiller reports institutional grants or contracts for clinical trials from AbbVie, Actinium, Actuate, Arog, Astellas, Bristol‐Myers Squibb, Celgene, Celator, Constellation, Daiichi‐Sankyo, Deciphera, Delta‐Fly, Forma, FujiFilm, Gamida, Genentech‐Roche, Geron, Incyte, Karyopharm, Kite/Gilead, Mateon, Onconova, Pfizer, PrECOG, Regimmune, Samus, Sangamo, Sellas, Stemline, Takeda, Tolero, Trovagene, Agios, Amgen, Jazz, Elevate Bio, Ono‐UK, Novartis, and Sanofi; personal fees from Ono, Pharma, Agios, Celgene, Incyte, Jazz, and Novartis; honoraria from Amgen, Jazz, Stemline, Kite, Bristol‐Myers Squibb, Sanofi, and Astellas; unpaid service as chair of the American Society of Hematology; and holds stock or stock options in Bristol‐Myers Squibb, Amgen, and Johnson & Johnson, all outside the submitted work. Selina Luger reports grants from Ariad, BioSight, Celgene, Cyclacel, Genentech, Kura, Onconova, Seattle Genetics, and Hoffman‐La Roche; and honoraria from Agios, Daiichi Sankyo Company, Jazz Pharmaceuticals, Pfizer, and Syros outside the submitted work. Gianluca Gaidano reports personal fees from AbbVie, Janssen, AstraZeneca, Bayer, and Beigene outside the submitted work. David Rizzieri institutional research support from Novartis during the course of the study; personal fees from AROG, Bayer, Celgene, Celltrion/TEVA, Mustang, Pfizer, Stemline, Kite, Incyte, Amgen, Cellectis, Chimerix, and Pharmacyclics outside the submitted work; honoraria from Incyte, Morphosys, Seattle Genetics, and Stemline outside the submitted work; and participation on a data safety monitoring board or advisory board for AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Incyte, Jazz, Kadmon, Kite, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Amgen, Acrobiotech, UCART, and Chimerix outside the submitted work. Tapan M. Kadia reports consulting fees from AbbVie, Agios, Amgen, Daiichi‐Sankyo, Genentech, Jazz, Liberum, Novartis, Pfizer, and Sanofi‐Aventis; grant research support from AbbVie, Agios, Amgen, Bristol‐Myers Squibb, Genentech, Jazz, Pfizer, Pulmotech, Cellenkos, Ascentage, Genfleet, Astellas, and AstraZeneca; and honoraria from Cure and Genzyme outside the submitted work. Marc Buyse owns stock in International Drug Development Institute, Belgium. Judy H. Chiao is an employee of Cyclacel. The remaining authors made no disclosures. Publisher Copyright: {\textcopyright} 2021 American Cancer Society.",
year = "2021",
month = dec,
day = "1",
doi = "10.1002/cncr.33828",
language = "English (US)",
volume = "127",
pages = "4421--4431",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "23",
}
