TY - JOUR
T1 - Gene expression profile predicts response to the combination of tosedostat and low-dose cytarabine in elderly AML
AU - Visani, Giuseppe
AU - Loscocco, Federica
AU - Dennis, Mike
AU - Zuffa, Eliana
AU - Candoni, Anna
AU - Sensi, Alberto
AU - Giannini, Barbara
AU - Musuraca, Gerardo
AU - Mianulli, Anna Maria
AU - Clavio, Marino
AU - Rocchi, Marco
AU - Gibellini, Davide
AU - Navari, Mohsen
AU - Gilkes, Amanda
AU - Piccaluga, Pier Paolo
AU - Isidori, Alessandro
N1 - Funding Information:
Acknowledgments The authors thank CTI Biopharma for providing tosedostat for the patients free of charge. The study was supported in part by AIL Pesaro Onlus.
Publisher Copyright:
© 2020 by The American Society of Hematology.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/10/19
Y1 - 2020/10/19
N2 - Tosedostat is an orally administered metalloenzyme inhibitor with antiproliferative and antiangiogenic activity against hematological and solid human cancers. Clinical activity has been demonstrated in relapsed acutemyeloid leukemia (AML). Thirty-three elderly patients with AML (median age, 75 years) received 120mgtosedostat orally once daily combinedwith subcutaneous low-dose cytarabine (20 mg twice per day for 10 days, up to 8 cycles), until disease progression. Inductionmortality was 12%. According to an intention-to-treat analysis, the complete remission (CR) rate was 48.5%, and thus the primary end point of the study was reached (expected CR, 25%). The partial remission rate was 6.1%,with an overall response rate of 54.5%. Furthermore, 4 of 33 patients had stable disease (median: 286 days). Themedian progression-free survival and overall survival (OS)were 203 days and 222 days, respectively. Responding patients had a longer median OS than nonresponding patients (P=.001). Amicroarray analysis performed in 29 of 33 patients identified 188 genes associated with clinical response (CR vs no CR). Three of them (CD93, GORASP1, CXCL16) were validated by quantitative polymerase chain reaction, which correctly classified 83% of the patients. Specifically, CR achievement was efficiently predicted by the gene expression patterns, with an overall accuracy exceeding 90%. Finally, a negative predictive value of 100% was validated in an independent series, thus representing the first molecular predictor for clinical response to a specific combination drug treatment for AML.
AB - Tosedostat is an orally administered metalloenzyme inhibitor with antiproliferative and antiangiogenic activity against hematological and solid human cancers. Clinical activity has been demonstrated in relapsed acutemyeloid leukemia (AML). Thirty-three elderly patients with AML (median age, 75 years) received 120mgtosedostat orally once daily combinedwith subcutaneous low-dose cytarabine (20 mg twice per day for 10 days, up to 8 cycles), until disease progression. Inductionmortality was 12%. According to an intention-to-treat analysis, the complete remission (CR) rate was 48.5%, and thus the primary end point of the study was reached (expected CR, 25%). The partial remission rate was 6.1%,with an overall response rate of 54.5%. Furthermore, 4 of 33 patients had stable disease (median: 286 days). Themedian progression-free survival and overall survival (OS)were 203 days and 222 days, respectively. Responding patients had a longer median OS than nonresponding patients (P=.001). Amicroarray analysis performed in 29 of 33 patients identified 188 genes associated with clinical response (CR vs no CR). Three of them (CD93, GORASP1, CXCL16) were validated by quantitative polymerase chain reaction, which correctly classified 83% of the patients. Specifically, CR achievement was efficiently predicted by the gene expression patterns, with an overall accuracy exceeding 90%. Finally, a negative predictive value of 100% was validated in an independent series, thus representing the first molecular predictor for clinical response to a specific combination drug treatment for AML.
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U2 - 10.1182/BLOODADVANCES.2020002305
DO - 10.1182/BLOODADVANCES.2020002305
M3 - Article
C2 - 33075137
AN - SCOPUS:85096186992
VL - 4
SP - 5040
EP - 5049
JO - Blood advances
JF - Blood advances
SN - 2473-9529
IS - 20
ER -