title: Bortezomib combined with low-dose cytarabine in Intermediate-2 and high risk myelodysplastic syndromes. A phase I/II Study by the GFM.
abstract: Marrow cells from patients with higher-risk myelodysplastic syndrome (MDS) exhibit constitutive nuclear factor (NF)-κB activation. The proteasome inhibitor, bortezomib, has limited efficacy as a single agent in acute myeloid leukaemia. Its activity on leukaemic cell lines is potentiated by chemotherapy. We treated 43 higher-risk MDS patients with bortezomib (1·5 mg/m(2) , days 1, 4, 8 and 11) and low dose cytarabine arabinoside (LDAC; 10 mg/m(2) , then 20 mg/m(2) from days 1-14), every 28 d for four cycles. Median follow-up was 29·7 months. Responses were seen in 12 of the 43 patients (28%), including complete response (CR, n = 1), marrow-CR (n = 3), partial response (PR, n = 5) and haematological improvement (HI, n = 3). Responses were seen in 12 (36%) of the 33 previously untreated patients (11% CR, 13% PR, 2·5% HI), compared to none in the 12 previously treated patients (P < 0·01). Responders had better overall survival (median 18·2 vs. 10 months). One CR and 3 marrow-CRs were seen in patients with complex karyotypes. Main toxicity was haematological, responsible for infection in six patients and bleeding in 3. Three patients with Grade 1-2 pre-treatment haematotoxicity developed Grade 3-4 toxicity. Neuropathy was seen in 12% of patients. The addition of bortezomib to LDAC in higher-risk MDS may improve results obtained with LDAC alone, especially in patients with unfavourable karyotypes.
authors.affiliation: Hopitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Shanti
authors.initials: S
authors.lastname: Natarajan-Amé
authors.affiliation: Hôtel Dieu de Paris, Assistance Publique Hôpitaux de Paris (AP-HP), Université Paris VI, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Park
authors.affiliation: Hôpital Avicenne, AP-HP, Université Paris XIII, Bobigny, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Ades
authors.affiliation: Institut Paoli Calmettes, Marseille, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.affiliation: Centre Hospitalier Universitaire (CHU) Brabois, Nancy, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Guerci-Bresler
authors.affiliation: Clinique Universitaire d'Hématologie, Hôpital Michallon, Grenoble, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Cahn
authors.affiliation: Institut Bergonié, Bordeaux, France.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Etienne
authors.affiliation: Centre Hospitalier Dupuytren, Limoges, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bordessoule
authors.affiliation: Hôpital de Jolimont, La Louviere, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Ravoet
authors.affiliation: Hôpital de l'Archet, Nice, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Legros
authors.affiliation: CHU de Caen, Caen, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Cheze
authors.affiliation: Centre Henri Becquerel, Rouen, France.
authors.forename: Aspasia
authors.initials: A
authors.lastname: Stamatoullas
authors.affiliation: CHU de Dijon, Dijon, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Berger
authors.affiliation: Centre Hospitalier Régional Universitaire d'Angers, Angers, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Institut Paoli Calmettes, Marseille, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Charbonnier
authors.affiliation: Centre Hospitalier Dupuytren, Limoges, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Chaury
authors.affiliation: Hôpital Avicenne, AP-HP, Université Paris XIII, Bobigny, France.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Braun
authors.affiliation: Hôpital Avicenne, AP-HP, Université Paris XIII, Bobigny, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.affiliation: Hôtel Dieu de Paris, Assistance Publique Hôpitaux de Paris (AP-HP), Université Paris VI, Paris, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Dreyfus
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000754:Anemia, Refractory, with Excess of Blasts / Q000188:drug therapy; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D003561:Cytarabine; D000069286:Bortezomib