title: Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS: Results from the nordic NMDSG08A phase II trial.
abstract: This prospective phase II study evaluated the efficacy of azacitidine (Aza)+erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo+granulocyte colony stimulation factors for >8 weeks and a transfusion need of 4 units over 8 weeks were included. Aza 75 mg m(-2) d(-1), 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received one cycle of Aza. Ten patients discontinued the study early, 7 due to adverse events including 2 deaths. Thirty-eight serious adverse events were reported, the most common being infection. Five patients achieved TI after six cycles and one after Aza+Epo, giving a total response rate of 20%. Mutational screening revealed a high frequency of recurrent mutations. Although no single mutation predicted for response, SF3A1 (n=3) and DNMT3A (n=4) were only observed in non-responders. We conclude that Aza can induce TI in severely anemic MDS patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations.
authors.affiliation: Division of Hematology, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Tobiasson
authors.affiliation: Department of Hematology, Rikshospitalet, Oslo, Norway.
authors.forename: I
authors.initials: I
authors.lastname: Dybedahl
authors.affiliation: Department of Hematology, Århus University Hospital, Århus, Denmark.
authors.forename: M S
authors.initials: MS
authors.lastname: Holm
authors.affiliation: Karolinska Institutet, Institution for Medicine, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Karimi
authors.affiliation: Department of Medicine, Sunderbyn Hospital, Luleå, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Brandefors
authors.affiliation: Department of Hematology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Garelius
authors.affiliation: Department of Medicine, SöDersjukhuset, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Grövdal
authors.affiliation: Department of Hematology, Herlev University Hospital, Copenhagen, Denmark.
authors.forename: I
authors.initials: I
authors.lastname: Högh-Dufva
authors.affiliation: Department of Hematology, Rigshospitalet University Hospital, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Grønbæk
authors.affiliation: Karolinska Institutet, Institution for Medicine, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Jansson
authors.affiliation: Department of Hematology, Odense University Hospital, Odense, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Marcher
authors.affiliation: Department of Hematology, Lund University Hospital, Lund, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Nilsson
authors.affiliation: Department of Medicine and University of Bergen, K2 Clinical Institute 2, Haukeland University Hospital, Bergen, Norway.
authors.forename: A O
authors.initials: AO
authors.lastname: Kittang
authors.affiliation: Division of Hematology, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Porwit
authors.affiliation: Division of Hematology, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Saft
authors.affiliation: Division of Hematology, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Möllgård
authors.affiliation: Division of Hematology, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Hellström-Lindberg