Low-Dose Decitabine Combined with Modified Bucy Is More Effective Conditioning Regimen for High-Risk Patients with Acute Myeloid Leukaemia/Myelodysplastic Syndrome
Authors: Tang Xiaowen , Cao Jing , Shi Xiaojing , Ge Ling , Sun Aining , Zhu Xiaming , Qiu Huiying , Jin Zhengming , Miao Miao , Fu Chengcheng , Ma Xiao , Chen Feng , Xue Shengli , Han Yue , Xue Mengxing , Mao Xinliang , Wu Depei 
Published: October 2019

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment options to hematologic malignancies. However, majority of patients with refractory or resistant AML/MDS can not achieve remission before transplantation. It is necessary to design a safe and effective conditioning regimen to reduce tumour burden, improve remission rates, decrease transplantation-related mortality, and improve disease-free survival (DFS) in patients with advanced acute myloid leukemia(AML) and myelodysplastic syndrom(MDS). One of the promising drugs of epigenetics is decitabine (DAC), which has a significant effect on a variety of hematologic malignancies including MDS and advanced AML. Furthermore, decitabine can not only up-modulate the tumor-associated antigen express on surface of leukemia cells to increase graft-versus-leukemia (GVL) effect but also can reduce the incidence of graft-versus-host disease (GVHD) by increase the number of regulatory T Cells (Tregs).

Objective: To investigate the security and efficacy of conditioning regimen containing low-dose decitabine combined with modified BUCY regimen for advanced AML/MDS patients, explore the role of immunomodulatory activity post transplantation and compared this regimen with conventional modified BUCY regimen.

Methods: Between January 2012 and March 2015, a total of 156 patients were enrolled in this retrospective study. In which, there were 46 patients who received a conditioning regimen of low-dose DAC and a modified BUCY regimen(DAC group) followed by allo-HSCT, and the second cohort consisted of 110 who only received a conventional modified BUCY regimen(Con group). Comparing the baseline of two groups, there were no significant difference except there were more advanced stage patients in DAC group(63% vs 32.7%,p=0.007). A modified BUCY conditioning regimen include semustine (250 mg/m2/d) for 1 d(-10d), cytarabine (2 g/m2 q12 h) for 2 d (-9 d to -8 d), busulfan (0.8 mg/kg/6 h) for 3 d (-7 d to -5 d), and cyclophosphamide (1.8 g/m2/d) for 2 d (-4 d to -3 d). Meanwhile, patients in the DAC group received the DAC treatment for 3 to 4 d with a total of 100 mg/m2 before modified BUCY regimen.

Results: In DAC group, all patients engrafted successfully, including 29/46(63%) non-remission (NR) patients. However, there were seven patients presented graft failure in Con group. The transplantation-related mortality (TRM) rate was significantly lower in DAC group(0% vs 13.6%, p=0.019). The median time of neutrophil recovery was 12(10-21)d vs 12(10-23)d, and platelet recovery was 13(10-35)d vs 14(9-40)d, respectively in DAC and Con group, and there were no significant differences. With the median follow-up of 277.5(39-985)d and 221(3-1237)d in two groups, the cumulative relapse rate(RR) was 38.2% vs 36.8% (p=0.951). The incidence rate of aGVHD was lower in DAC group(26.7% vs 46.8%, p=0.034), while there were no diference in the incidence rate of cGVHD(68.4% vs 70.7%, p=0.598). Compared with Con group, the estimated 2-year overall survival (2yr-OS) rate and 2 year disease-free survival (2yr-DFS) rate were both higher in DAC group(2yr-OS:45.6% vs 75.3%, p=0.007, Fig 1; 2yr-DFS:39.1% vs 51.5%, p=0.076). Furtheremore, for patients in advanced stage before transplant, the estimated 2yr-OS was 37.2% vs 72.7%(p=0.009) and 2yr-DFS rate was 38.5% vs 49.8%(p=0.051), respectively. For AMLs, the estimated 2yr-OS rate in DAC and Con group was 75.0% vs 43.0%(p=0.034), and for advanced stage AMLs, the estimated 2yr-OS rate was 66.1% vs 29.7%( p=0.031). Regarding the early relapse rate(RR) of 6 months post transplant, DAC group were less than that of Con group(11.5% vs 35.3%, p=0.124).

Conclusion:

1. Low-dose decitabine combined with modified BUCY is a safe and effective conditioning regimen for high-risk patients with AML/MDS with low toxicity and well tolerance.

2. 100% NR patients of DAC group achieved complete remission with full donor chimerism at d30.

3.Comparing with Con group, patients in DAC group had ralative lower incidence of aGVHD, TRM and RR but relative higher estimated 2-yr OS and DFS, especially for advanced stage patients.

Disclosures

No relevant conflicts of interest to declare.