Decitabine Combined With Chemotherapy For The Treatment Of Refractory Acute Myeloid Leukemia: a Pilot Phase 1 Clinical Study
Authors: Pan Ling , Chen Meng , Jia Yongqian , Cui Xu , Niu Ting , Chang Hong , Ma Hongbing , Li Jianjun , Gong Yuping , Chen Xinchuan , Liu Ting 
Published: October 2019

Abstract

Background
The demethylating agent decitabine (DCA) had been employed in the treatment of acute myeloid leukemia (AML) as epigenetic therapy. A phase 3 trial for older patients (pts) with newly diagnosed AML had clearly demonstrated that DAC alone was more effective than ‘treatment choice’. However, outcomes are poorer in refractory AML with DAC alone or chemotherapy alone. Since combine index of DAC and Ara-C had been reported in preclinical study, the efficacy and safety of DAC combined with chemotherapy for pts with refractory AML were investigated in this pilot phase 1 clinical study.

Patients
A total of 23 pts (8 female and 15 male) with AML were enrolled from Jan 4 2012 to June 30 2013. According to World Health Organization (WHO) classification criteria, 2 pts were diagnosed as AML-M1, 6 were AML-M2, 4 were AML-M4, 7 were AML-M5 and 4 were AML-M6, among whom 6 pts were with overt myelodysplastic syndrome (MDS) history. Median age was 61 years (range, 36-78). The Eastern Cooperative Oncology Group (ECOG) score was 1 in 5 pts, 2 in 13 pts and 3 in 5 pts. Median courses of disease was 9 months (range, 3 months to over 4 years). Cytogenetics at diagnosis according to National Comprehensive Cancer Network (NCCN) guideline was poor-risk in 7 pts, not poor-risk in 12 pts and without examination of cytogenetic abnormality in 4 pts. 19 pts had received at least 2 standard courses of chemotherapy and failed to achieve complete remission (CR), 4 pts could not tolerate standard chemotherapy.

Methods
At the beginning, 4 pts were given DAC 15 mg/m2/day intravenous (IV) over 90 minutes from days 1 to 5, and chemotherapy was given 48 hours after the first dose of DAC. Two pts were enrolled into DAC with standard DA regimen, and another two into DAC with AA (aclacinomycin 10 mg/d IV days 3 to 6 and Ara-C 10mg/m2 ih bid days 3 to 9). As DAC with DA regimen was poorly tolerated, then the other 19 pts were enrolled into 2 schedules of DAC plus AA. Schedule 1(12Pts) was DAC 15 mg/m2/day IV 90 minutes qd, days 1 to 5; schedule 2(7Pts) was DAC 15 mg/m2 IV 90 minutes bid, days 1 to 3(According to a special situation in China, 50mg DCA was divided into two equal amount, from which the needed amount was used separately in a interval of 4 hours) The therapy were given at least 2 courses, and continued until pts achieved CR. During treatment with DAC and chemotherapy, pts were given best available support care including blood component transfusion, preventing infection and granulocyte colony-stimulating factor (G-CSF) subcutaneous injection.

Results
Among the 23 pts, 11 (47.8%) achieved CR or bone marrow remission without platelet recovered(CRp), 3 achieved partial remission (PR). The overall response rate (ORR) was 60.9%. Up to now, 16 pts were still alive, 6 were dead, and one lost follow-up. For the 6 death, 4 were caused by disease progression, one by severe infection, and one in CR condition died from food obstruction in the laryngeal which was a very rare situation. The half-year overall survival rate (OS) was 64.7%. For pts who achieved CR/CRp, the half-year OS was 88.9%. 10 pts (43.5%) were with 3 to 4 grade of myelosuppression; 16 pts (69.6%) developed infection. There was no statistically significant difference in efficacy (62.5% VS 60%) and safety between the two schedules of DAC, and also no statistically significant difference in subgroups, in terms of WHO classification, age (distinguished by age of 60), pre-treatment courses, ECOG and NCCN cytogenetics.

Conclusion
DAC combined with AA (aclacinomycin and Ara-C) was efficient and tolerable for refractory AML pts, and the advantage of the 2 DAC schedules should be evaluated by further study. Results of subgroup analysis indicated that DAC combined with AA could overcome poor prognosis factors such as WHO classification, elder age, pre-treatment courses, ECOG score and poor-risk cytogenetic abnormalities.

Disclosures:
No relevant conflicts of interest to declare.