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.

Gene expression profile predicts response to the combination of tosedostat and low-dose cytarabine in elderly AML / Visani, G.; Loscocco, F.; Dennis, M.; Zuffa, E.; Candoni, A.; Sensi, A.; Giannini, B.; Musuraca, G.; Mianulli, A. M.; Clavio, M.; Rocchi, M.; Gibellini, D.; Navari, M.; Gilkes, A.; Piccaluga, P. P.; Isidori, A.. - In: BLOOD ADVANCES. - ISSN 2473-9529. - 4:20(2020), pp. 5040-5049. [10.1182/BLOODADVANCES.2020002305]

Gene expression profile predicts response to the combination of tosedostat and low-dose cytarabine in elderly AML

Candoni A.;
2020

Abstract

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.
2020
4
20
5040
5049
Gene expression profile predicts response to the combination of tosedostat and low-dose cytarabine in elderly AML / Visani, G.; Loscocco, F.; Dennis, M.; Zuffa, E.; Candoni, A.; Sensi, A.; Giannini, B.; Musuraca, G.; Mianulli, A. M.; Clavio, M.; Rocchi, M.; Gibellini, D.; Navari, M.; Gilkes, A.; Piccaluga, P. P.; Isidori, A.. - In: BLOOD ADVANCES. - ISSN 2473-9529. - 4:20(2020), pp. 5040-5049. [10.1182/BLOODADVANCES.2020002305]
Visani, G.; Loscocco, F.; Dennis, M.; Zuffa, E.; Candoni, A.; Sensi, A.; Giannini, B.; Musuraca, G.; Mianulli, A. M.; Clavio, M.; Rocchi, M.; Gibellin...espandi
File in questo prodotto:
File Dimensione Formato  
advancesadv2020002305.pdf

Open access

Tipologia: Versione pubblicata dall'editore
Dimensione 1.31 MB
Formato Adobe PDF
1.31 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1294008
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 5
  • ???jsp.display-item.citation.isi??? 6
social impact