Bortezomib combined with low‐dose cytarabine in Intermediate‐2 and high risk myelodysplastic syndromes. A phase I/II Study by the GFM

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/m2, days 1, 4, 8 and 11) and low dose cytarabine arabinoside (LDAC; 10 mg/m2, then 20 mg/m2 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.