Research Papers:

Reassessing the role of high dose cytarabine and mitoxantrone in relapsed/refractory acute myeloid leukemia

Jonathan Canaani, Meital Nagar, Gabriel Heering, Chen Gefen, Ronit Yerushalmi, Noga Shem-Tov, Yulia Volchek, Drorit Merkel, Abraham Avigdor, Avichai Shimoni, Ninette Amariglio, Gidi Rechavi and Arnon Nagler _

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Oncotarget. 2020; 11:2233-2245. https://doi.org/10.18632/oncotarget.27618

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Jonathan Canaani1, Meital Nagar1, Gabriel Heering1, Chen Gefen1, Ronit Yerushalmi1, Noga Shem-Tov1, Yulia Volchek1, Drorit Merkel1, Abraham Avigdor1, Avichai Shimoni1, Ninette Amariglio1, Gidi Rechavi1 and Arnon Nagler1

1 Hematology Division, Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel

Correspondence to:

Arnon Nagler,email: [email protected]

Keywords: acute myeloid leukemia; FLT3-ITD; next-generation sequencing

Received: January 30, 2020     Accepted: May 14, 2020     Published: June 09, 2020


A substantial segment of patients with acute myeloid leukemia (AML) will relapse following an initial response to induction therapy or will prove to be primary refractory. High-dose cytarabine and mitoxantrone (HiDAC/MITO) is an established salvage therapy for these patients. We studied all adult patients with relapsed/refractory (R/R) AML who were treated with HiDAC/MITO in our center between the years 2008-2017. To determine whether responding patients harbored a unique molecular signature, we performed targeted next-generation sequencing (NGS) on a subset of patients. The study cohort consisted of 172 patients with a median age of 54 years (range 18–77). The composite complete remission rate was 58%; 11 patients (6%) died during salvage therapy. Median survival was 11.4 months with a 1-year survival rate of 48%. In multivariate analysis favorable risk cytogenetics [Odds ratio (OR)=0.34, confidence interval (CI) 95%, 0.17–0.68; P = 0.002], and de-novo AML (OR = 0.4, CI 95%, 0.16–0.98; P = 0.047) were independently associated with a favorable response. Patients who attained a complete remission had a median survival of 43.7 months compared with 5.2 months for refractory patients (p < 0.0001). Neither the FLT3-ITD and NPM1 mutational status nor the indication for salvage therapy significantly impacted on the response to HiDAC/MITO salvage. NGS analysis identified 20 different mutations across the myeloid gene spectrum with a distinct TP53 signature detected in non-responding patients. HiDAC/MITO is an effective salvage regimen in R/R AML, however patients with adverse cytogenetics or secondary disease may not benefit as much from this approach.

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