Could Anthracycline be Replaced in Chemotherapy for Acute Myeloid Leukemia? Randomized Clinical Trial of Homoharringtonine As Frontline Agent to Treat Pediatric AML
Authors: Shen Shuhong , Wang Xiang , Tang JingYan , Xue Huiliang , Chen Jing , Tang Yanjing , Gu Long-Jun 
Published: October 2019

Method: From Jan. 1st , 2009 to Dec. 31st, 2013, 153 patients was diagnosed to be acute myeloid leukemia (non acute promyelocytic leukemia) (AML). 152 of them were willing to be recruited in the randomized clinical trial. After informed consent, randomly divided group A and group B were treated with regimens A and B accordingly. In regimen A, total 240mg/m2 daunorubicin and 60 mg/m2 mitoxantrone were given in total 6 cycles of intensive chemotherapy along with cytarabine and/or etopside; while in regimen B, the anthracycline was substituted for homoharringtonine except the first cycle, ie, only 120 mg/m2 daunorubicin was used in regimen B. All the patients recruited were registered to Pediatric Oncology Network Database (POND) provided by St. Jude Children's Research Hospital once the diagnose was made and the consent form was signed. Regular follow-up was done every 3 months for patients off treatment. The end point of this follow-up was 2014/6/30.

Besides the regular cytogenetic study of all cases, c-kit mutations in exon 8 and exon 17 were screened by direct sequencing.

Results: There were 82 and 70 cases de novo AML in group A and group B respectively. The distribution of FAB subtypes and the major cytogenetic abnormalities was similar (p>0.1) between the groups. For the first course in both regiment were the same, the similarity of the first course remission rate (p=0.2), hematological changes and the febrile neutropenia occurrence in this cycle of chemotherapy may reflect the intrinsic accordance of two groups. Analyzing the survival function of the protocol, the 3-year Events free survival (EFS) was 59.3±5.1%, 3 year overall survival rate (OS) was 73 ± 4.8%, and 25.6 ± 5% patients finally relapsed. Comparing the group A and the group B, EFS, OS and relapse rate were similar: 62.6 ± 6.8% Vs 58 ± 7.5%, 76.1 ± 6.3% Vs 70.1 ± 7.2%, and 27.7 ± 7% Vs 28.3 ± 7.4%, P values were more than 0.1. Interestingly, except the first cycle induction therapy, all the regiment B course had less hematological toxicity and less incidence and severity of febrile neutropenia. Group A Vs group B, the average duration of neutrophil count <0.5 x 109/L in each course was 11.3 ± 0.8 Vs 8.5 ± 0.7 days, p=0.0004; duration of platelet count <50 x 109/L was 12.4 ± 1.5 Vs 7.8 ± 0.9 days, p=0.0003; while the incidence of febrile neutropenia was 48% Vs 23% p<0.0001 and the severe infection was occurred in 2.9% group A patients, compared to only in 0.5% group B patients, p=0.042.

During prognosis analysis, we surprisingly found that patients with AML1-ETO fusion gene, which was well accepted as a favorable prognosis predictor, often have worse outcome: the 3-year EFS was only 43.4 ± 8.6%, much lower than which of the Non-AML1-ETO patient (68.3±6.1%, p=0.024). It might be partially due to the higher frequency of c-Kit mutation: in these 43 AML1-ETO positive patients, 18 (41.8%)were found to have mutation in c-Kit at exon 8 and exon 17. These mutants usually accompanied with poorer survival especially those with mutation at exon 8 and D816. The 3-year EFS of patients with these two kinds of mutation were 13 ± 12.1% compared to the other AML1-ETO+ patients' 57.2 ± 10.3%. But still, the outcome of these AML1-ETO+ patients without bad c-kit mutation were worse than patients with normal karyotype, which had 3-EFS 76.4 ± 10.7%. In this study, the survival feature of patients with AML1-ETO was regimenting independent.

Conclusion: 1) The efficacy of homoharringtonine contacting regiment was similar to the standard anthracycline contacting regiment. The former usually had less toxicity. It may helpful for improving the patient's quality of life, reduce the economic burden of patients' family without compromising the survival. 2) For Chinese children, AML1-ETO fusion gene is not a good prognosis predictor, at least in part, due to more conmen c-Kit mutation.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.