This study evaluated the efficacy and toxicities of DCAG (standard dose cytarabine [100 mg/m2 q12 hrs for 5 days] and increased dose of aclarubicin hydrochloride [20 mg/d for 5 days]) relative to standard dose chemotherapy regimens (control) for non-elderly patients with newly diagnosed AML (aged 14–60 years). Pretreatment genetic testing was also conducted. The DCAG and IA induction chemotherapy groups were statistically similar with regard to complete remission rate after the first cycle, OS, and EFS.
Previous reports6,26 showed that AML patients treated with decitabine only responded poorly. Most patients required at least two monthly cycles to achieve a clinical response, and many needed three or more cycles. The present study showed that induction therapy combining decitabine with a modified CAG regimen was safe, but with a complete remission rate of 54.7% after two cycles of induction chemotherapy. The DCAG regimen was well tolerated, with a low early-death rate and short duration of pancytopenia. The clinical response toward DCAG motivated us to investigate further for biomarkers of response and prognosis.
The spectrum of frequent mutations in the AML patients of our study is similar to that reported for other large AML populations.27 Of the 72 identified genes, 10 genes in our study were mutated in >5% of the patients. The two most commonly identified mutations in the present study were in CEBPA (19.9%) and FLT3-ITD (16.1%), and then mutations in NRAS (13.0%), NPM1 (12.4%), DNMT3A (11.2%), ASXL1 (8.7%), and IDH2 (8.1%). The genes with a mutation frequency of >10% (CEBPA, FLT3-ITD, NPM1, and DNMT3A) were similarly reported in studies by Lin et al27 and Mccurdy and Levis.28 Despite the prevalence of dozens of these recurrent mutations in AML, only NPM1, CEBPA, FLT3-ITD, and TP53 have been used in widely accepted risk-stratification schemas, such as the NCCN guidelines.
The Fms-like tyrosine kinase 3 (FLT3) gene has been an important marker in acute myeloid leukemia, where FLT3 mutations have been associated with clinical prognosis and treatment.29–31 Studies have found that survival for FLT3-ITD AML is improved by allogeneic stem cell transplantation in CR1.29–32In the present study, 9 FLT3-ITD-positive patients in the DCAG group, and 9 FLT3-ITD-positive patients in the IA group, received allogeneic peripheral blood stem cell transplantation. In the DCAG group, mutations of FLT3-ITD were identified as significantly associated with poor OS and poor EFS. The outcomes associated with FLT3-ITD mutations in the DCAG group contrast with those of patients who received IA chemotherapy, in whom the presence of FLT3-ITD mutations had no effect on OS or EFS. As there are 15 patients with a FLT3-ITD mutation in the DCAG group and 11 in the IA group, more studies are warranted to verify our results.
In conclusion, the DCAG and IA induction chemotherapy groups were statistically similar with regard to complete remission rate after the first cycle, OS, and EFS. However, after the second cycle, the complete remission rate of the DCAG group was significantly lower than that of the IA reference. The DCAG regimen was well tolerated, with a low early-death rate and short duration of pancytopenia. Clinical sequencing provides important information for accurate prognostication in patients. Recommendations for chemotherapy should be based on both molecular mutations and clinical features.
This work was partially supported by grants from the Beijing Nova Program (2011114), the National Natural Science Foundation of China (Nos. 81770203, 30971297, 81102242, 81000221, 81270610, 81470010, 81170518, 81370666, and 90919044), the Beijing Natural Science Foundation of China (No. 7102147, 7172200, and 7132217), the Capital’s Funds for Health Improvement and Research (No. 2016-1-4082), and Hainan Provincial Natural Science Foundation of China (818MS157).
The authors report no conflicts of interest in this work.
Qingyu Xu,1* Mengzhen Wang,1* Yang Xiao,1* Longcan Cheng,2 Honghua Li,1 Wenrong Huang,1 Junhui Mei,1 Yu Jing,1 Jian Bo,1,2 Daihong Liu,1 Li Yu1
1Department of Hematology, Chinese PLA General Hospital, Beijing 100853, People’s Republic of China; 2Department of Hematology, Hainan Branch of Chinese PLA General Hospital, Sanya, Hainan 572013, People’s Republic of China
*These authors contributed equally to this work
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Source: OncoTargets and Therapy.
Originally published June 28, 2019.
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