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Clinical Trial
. 2021 Dec 1;127(23):4421-4431.
doi: 10.1002/cncr.33828. Epub 2021 Aug 23.

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

Hagop M Kantarjian  1 , Kebede H Begna  2 , Jessica K Altman  3 , Stuart L Goldberg  4 , Mikkael A Sekeres  5 , Stephen A Strickland  6 , Martha L Arellano  7 , David F Claxton  8 , Maria R Baer  9 , Marc Gautier  10 , Ellin Berman  11 , Karen Seiter  12 , Scott R Solomon  13 , Gary J Schiller  14 , Selina M Luger  15 , Aleksandra Butrym  16 , Gianluca Gaidano  17 , Xavier G Thomas  18 , Pau Montesinos  19 , David A Rizzieri  20 , Donald P Quick  21 , Parameswaran Venugopal  22 , Rakesh Gaur  23 , Lori J Maness  24 , Tapan M Kadia  1 , Farhad Ravandi  1 , Marc E Buyse  25 , Judy H Chiao  26
Affiliations
Clinical Trial

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

Hagop M Kantarjian et al. Cancer. .

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.

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Conflict of interest statement

Conflict of Interest Statement

Hagop M. Kantarjian reports research grants and honoraria from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, Novartis, Pfizer and Sanofi; honoraria from Actinium (Advisory Board), Adaptive Biotechnologies, Aptitude Health, BioAscend, Delta Fly, Janssen Global, Oxford Biomedical and Takeda. Stephen Strickland reports AbbVie, ArcherDx, Genentech, Incyte, Kura Oncology, Novartis, Pfizer, and Syros; Research Funding (paid t institution): Sunesis. Marc Buys reports being a shareholder of IDDI (International drug Development Institute, Belgium). Tapan M. Kadia reports consulting fees from AbbVie, Agios, Daiichi Sankyo, Genetech,Jazz, Liberum, Novartis, Phizer, Sanofi-Aventis; Grant Research Support from AbbVie, Amgen, BMS, Genetech, Jazz, Pfizer, Pulmotech, Cellenkos, Ascentage, Genfleet, Astellas, Astrazeneca; Speaker’s Bureau from Cure and honoraria from Genzyme. The other authors made no disclosures.

Figures

Figure 1
Figure 1
Kaplan Meier Survival Curve – ITT population
Figure 2
Figure 2
Survival Analysis in Subgroups
See this image and copyright information in PMC

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