Erythroid response and decrease of WT1 expression after proteasome inhibition by bortezomib in myelodysplastic syndromes.
NF-kB is reported to be constitutively activated in a percentage of high-risk myelodysplastic syndrome carrying cytogenetic aberrations. Only few data are reported on the use of proteasome inhibitors in this subset of patients. We performed a study on efficacy and safety of bortezomib as a single agent in patients with myelodysplastic syndromes (MDS). Bortezomib was administered at 1.3mg/m(2) with a 1, 4, 8, 11-day schedule every 28 days, in 19 patients with IPSS low/intermediate 1 or intermediate2/high risk. Six out of 19 patients received all planned eight cycles. Hematologic toxicity was recorded in all patients, especially grade 3/4 neutropenia and grade 3/4 thrombocytopenia; non-hematologic side effects were recorded in 7 patients, but events were all of grade 1/2 toxicity. According to IWG 2006 criteria, 4 out of 19 patients (21%) achieved erythroid response and 9 patients (47%) showed stable disease. In patients with erythroid response bone marrow WT1 levels decreased from a median of 109 copies at baseline to a median of 14 copies at the end of treatment, whereas in patients with stable disease, median WT1 copies increased either in bone marrow and peripheral blood. In conclusion, bortezomib used alone in MDS shows modest hematologic efficacy but appears to affect the WT1 gene expression, which is typically increased in these diseases.
Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Via Benevento 6, 00161 Rome, Italy. alimena@bce.uniroma1.it
Giuliana
G
Alimena
Massimo
M
Breccia
Pellegrino
P
Musto
Daniela
D
Cilloni
Fiorella
F
D'Auria
Roberto
R
Latagliata
Grazia
G
Sanpaolo
Enrico
E
Gottardi
Giuseppe
G
Saglio
Franco
F
Mandelli
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001897:Boronic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D041905:Erythroid Cells / Q000187:drug effects*; D005260:Female; D005334:Fever / Q000139:chemically induced; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000009:adverse effects / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D025721:WT1 Proteins / Q000235:genetics*
D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D025721:WT1 Proteins; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex