Gene expression profile predicts response to the combination of tosedostat and low-dose cytarabine in elderly AML
Mianulli, A. M.
Piccaluga, P. P.
AffiliationHematology and Stem Cell Transplant Center, Azienda Ospedaliera Ospedali Riuniti Marche Nord (AORMN), Pesaro, Italy.
MetadataShow full item record
AbstractTosedostat is an orally administered metalloenzyme inhibitor with antiproliferative and antiangiogenic activity against hematological and solid human cancers. Clinical activity has been demonstrated in relapsed acute myeloid leukemia (AML). Thirty-three elderly patients with AML (median age, 75 years) received 120 mg tosedostat orally once daily combined with subcutaneous low-dose cytarabine (20 mg twice per day for 10 days, up to 8 cycles), until disease progression. Induction mortality 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). The median 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). A microarray 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. This trial has been registered at the European Medicines Agency and on the European Clinical Trials Database (https://www.clinicaltrialsregister.eu) as #2012-000334-19.
CitationVisani G, Loscocco F, Dennis M, Zuffa E, Candoni A, Sensi A, et al. Gene expression profile predicts response to the combination of tosedostat and low-dose cytarabine in elderly AML. Blood Adv. 2020;4(20):5040-9.
- Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high-risk MDS.
- Authors: Mawad R, Becker PS, Hendrie P, Scott B, Wood BL, Dean C, Sandhu V, Deeg HJ, Walter R, Wang L, Myint H, Singer JW, Estey E, Pagel JM
- Issue date: 2016 Jan
- Low-dose lenalidomide plus cytarabine in very elderly, unfit acute myeloid leukemia patients: Final result of a phase II study.
- Authors: Visani G, Ferrara F, Di Raimondo F, Loscocco F, Fuligni F, Paolini S, Zammit V, Spina E, Rocchi M, Visani A, Piccaluga PP, Isidori A
- Issue date: 2017 Nov
- Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL): a randomised open-label phase 2 study.
- Authors: Cortes J, Feldman E, Yee K, Rizzieri D, Advani AS, Charman A, Spruyt R, Toal M, Kantarjian H
- Issue date: 2013 Apr
- Twice-daily fludarabine and cytarabine combination with or without gentuzumab ozogamicin is effective in patients with relapsed/refractory acute myeloid leukemia, high-risk myelodysplastic syndrome, and blast- phase chronic myeloid leukemia.
- Authors: Jabbour E, Garcia-Manero G, Cortes J, Ravandi F, Plunkett W, Gandhi V, Faderl S, O'Brien S, Borthakur G, Kadia T, Burger J, Konopleva M, Brandt M, Huang X, Kantarjian H
- Issue date: 2012 Aug
- Efficacy and feasibility of cyclophosphamide combined with intermediate- dose or high-dose cytarabine for relapsed and refractory acute myeloid leukemia (AML).
- Authors: Schnetzke U, Fix P, Spies-Weisshart B, Schrenk K, Glaser A, Fricke HJ, La Rosée P, Hochhaus A, Scholl S
- Issue date: 2014 Aug