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Phase I trial of plerixafor combined with decitabine in newly diagnosed older patients with acute myeloid leukemia.

ABSTRACT: Acute myeloid leukemia carries a dismal prognosis in older patients. The objective of this study was to investigate the safety and efficacy of decitabine combined with the CXCR4 antagonist plerixafor in newly diagnosed older patients with acute myeloid leukemia and to evaluate the effects of plerixafor on leukemia stem cells. Patients were treated with monthly cycles of decitabine 20 mg/m2 days 1-10 and escalating doses of plerixafor (320-810 mcg/kg) days 1-5. Sixty-nine patients were treated, with an overall response rate of 43%. Adverse karyotype did not predict response (P=0.31). Prior hypomethylating agent treatment was the strongest independent predictor of adverse overall survival (hazard ratio 3.1; 95%CI: 1.3-7.3; P=0.008) and response (14% in previously treated patients, 46% in treatment naïve; P=0.002). As expected, the most common toxicities were myelosuppression and infection. Plerixafor induced mobilization of leukemia stem and progenitor cells, but did not cause clinically significant hyperleukocytosis. Reduction in leukemia stem cells appeared to correlate with duration of response. Plerixafor can be safely added to decitabine in poor-prognosis, elderly acute myeloid leukemia patients. The maximum tolerated dose of the combination was 810 mcg/kg. While mobilization of leukemia stem cells was observed in some patients, the clinical benefit of adding plerixafor was uncertain. This trial was registered at clinicaltrials.gov identifier: 01352650.

SUBMITTER: Roboz GJ

PROVIDER: S-EPMC6068018 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Phase I trial of plerixafor combined with decitabine in newly diagnosed older patients with acute myeloid leukemia.

Roboz Gail J GJ Ritchie Ellen K EK Dault Yulia Y Lam Linda L Marshall Danielle C DC Cruz Nicole M NM Hsu Hsiao-Ting C HC Hassane Duane C DC Christos Paul J PJ Ippoliti Cindy C Scandura Joseph M JM Guzman Monica L ML

Haematologica 20180503 8

Acute myeloid leukemia carries a dismal prognosis in older patients. The objective of this study was to investigate the safety and efficacy of decitabine combined with the CXCR4 antagonist plerixafor in newly diagnosed older patients with acute myeloid leukemia and to evaluate the effects of plerixafor on leukemia stem cells. Patients were treated with monthly cycles of decitabine 20 mg/m<sup>2</sup> days 1-10 and escalating doses of plerixafor (320-810 mcg/kg) days 1-5. Sixty-nine patients were ...[more]

PMID: 29724902

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Project description:BackgroundAcute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is associated with several biomarkers. Decitabine, a deoxyribonucleic acid (DNA) methyltransferase (DNMT) inhibitor, combined with cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor (DCAG), has been used in patients newly diagnosed with AML. This regimen has been especially used in older and fragile patients who are immunocompromised or have co-morbidities, as well as those with specific gene mutations. However, the integration of molecular risk stratification and treatment guidance for the DCAG regimen has not been well defined. Therefore, this study aimed to investigate the genetic mutations associated with AML and establish appropriate treatment strategies for patients newly diagnosed with AML.MethodsThis study analyzed the clinical data and genetic mutations based on next-generation sequencing (NGS) in 124 newly diagnosed patients with AML who received the DCAG regimen at the People's Liberation Army (PLA) General Hospital from January 2008 to August 2020. Factors associated with the cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) in patients newly diagnosed with AML were analyzed.ResultsThe most adverse prognosis of DCAG-treated patients was observed in those with FLT3-ITD, KIT, PTPN11, GATA2, or IDH1 mutations during univariable analysis, whereas PTPN11 mutation was solely significant in multivariable analysis, with an increased likelihood of CIR (P = 0.001) and reduced LFS duration (P = 0.077). Hyperleukocytosis was maintained as an independent risk factor for increased CIR risk (P = 0.044) and decreased LFS duration (P = 0.042) in multivariable analysis. In this study, we validated the risk classification of patients with AML receiving an epigenetic modifier-based induction regimen across a broad age range.ConclusionNGS demonstrated a dismal overall outcome in patients with the rare PTPN11 mutations, indicating the need for new therapies that target this high-risk subtype of AML. These results offer a potential molecular stratification and treatment guidance for patients with AML.

Project description:BackgroundDecitabine has been widely used to treat acute myeloid leukemia (AML); however as AML is a heterogeneous disease, not all patients benefit from decitabine. This study aimed to identify markers for predicting the response to decitabine.MethodsAn intersection of in vitro experiments and bioinformatics was performed using a combination of epigenetic and transcriptomic analysis. A tumor-suppressor gene associated with methylation and the response to decitabine was screened. Then the sensitivity and specificity of this marker in predicting the response to decitabine was confirmed in 54 samples from newly diagnosed AML patients treated with decitabine plus IA regimen in a clinical trial (ChiCTR2000037928).ResultsIn vitro experiments showed that decitabine caused hypomethylation and upregulation of BTG1, while downregulation of BTG1 attenuated the inhibitory effect of decitabine. In newly diagnosed AML patients who received decitabine plus IA regimen, the predictive value of BTG1 to predict complete remission (CR) was assigned with a sensitivity of 86.7% and a specificity of 100.0% when BTG1 expression was < 0.292 (determined using real-time quantitative PCR), with area under the curve (AUC) = 0.933, P = 0.021. The predictive value of BTG1 to predict measurable residual disease (MRD) negativity was assigned with a sensitivity of 100.0% and a specificity of 80.0% when BTG1 expression was < 0.292 (AUC = 0.892, P = 0.012). Patients were divided into low and high BTG1 expression groups according to a cutoff of 0.292, and the CR rate of the low-expression group was significantly higher than that of the high-expression group (97.5% vs. 50%, P < 0.001).ConclusionsLow expression of BTG1 was associated with CR and MRD negativity in newly diagnosed AML patients treated with a decitabine-containing regimen, suggesting that BTG1 is a potential marker for predicting the response to decitabine in newly diagnosed AML.Clinical trial registrationChiCTR2000037928.

Dataset Information

Phase I trial of plerixafor combined with decitabine in newly diagnosed older patients with acute myeloid leukemia.

Publications

Phase I trial of plerixafor combined with decitabine in newly diagnosed older patients with acute myeloid leukemia.

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