Abstract
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.
Highlights
While most patients with acute myeloid leukemia (AML) will achieve an initial remission following induction chemotherapy [1], up to 40% of patients will experience induction failure [2,3,4,5], and nearly half of the younger patient population (60 years or younger) achieving a first complete remission (CR1) will eventually relapse with older patients experiencing relapse rates reaching upwards to 80% [6, 7]
Patients received donor lymphocyte infusion (DLI) at a median of 3 days after HiDAC/MITO with a median dose of administered cells of 9.6 × 107 CD3/kg. 8/13 patients achieved CR/complete remission with incomplete hematologic recovery (CRi) (62%), no statistically significant difference in terms of response was observed between patients given DLI and those not receiving DLI (p = NS)
Whereas targeting of molecular aberrations and epigenetic dysregulation is an area of flux in AML, standard cytotoxic chemotherapy remains the benchmark for evaluating the efficacy and safety of new therapies in AML
Summary
While most patients with acute myeloid leukemia (AML) will achieve an initial remission following induction chemotherapy [1], up to 40% of patients will experience induction failure [2,3,4,5], and nearly half of the younger patient population (60 years or younger) achieving a first complete remission (CR1) will eventually relapse with older patients experiencing relapse rates reaching upwards to 80% [6, 7] Prognosis for this clinically challenging patient segment is quite poor with long term survival being realized in only a small fraction of patients treated both with intensive and nonintensive approaches [8,9,10]. As generation sequencing (NGS) is gaining increased acceptance as an innovative modality in AML for genomic classification [29], risk stratification [30], and tracking of minimal residual disease [31], we sought to investigate whether NGS profiling can predict for treatment response in our patients treated with HiDAC/ MITO
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