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: Shanti Natarajan-Amé, Sophie Park, Lionel Ades, Norbert Vey, Agnès Guerci-Bresler, Jean-Yves Cahn, Gabriel Etienne, Dominique Bordessoule, Christophe Ravoet, Laurence Legros, Stephane Cheze, Aspasia Stamatoullas, Elisabeth Berger, Aline Schmidt, Aude Charbonnier, Marie-Pierre Chaury, Thorsten Braun, Pierre Fenaux, Francois Dreyfus, Groupe Francophone des Myélodysplasies (GFM)
• Journal: British journal of haematology (Br J Haematol) Vol. 158 Issue 2 Pg. 232-237 (Jul 2012) ISSN: 1365-2141 [Electronic] England
• PMID: 22571447 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study)
• Copyright: © 2012 Blackwell Publishing Ltd.

Chemical References

• Boronic Acids
• Pyrazines
• Cytarabine
• Bortezomib

Topics

• Aged
• Aged, 80 and over
• Anemia, Refractory, with Excess of Blasts (drug therapy)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Boronic Acids (administration & dosage, adverse effects, therapeutic use)
• Bortezomib
• Cytarabine (administration & dosage, adverse effects, therapeutic use)
• Drug Administration Schedule
• Drug Therapy, Combination
• Female
• Follow-Up Studies
• Humans
• Leukemia, Myeloid, Acute (drug therapy)
• Male
• Middle Aged
• Myelodysplastic Syndromes (drug therapy)
• Pyrazines (administration & dosage, adverse effects, therapeutic use)
• Survival Analysis
• Treatment Outcome