Decitabine-based chemotherapy followed by haploidentical lymphocyte infusion improves the effectiveness in elderly patients with acute myeloid leukemia

Abstract

In this study, we first initiated a multicenter, single-arm, phase-II clinical trial using decitabine (DAC) (20mg/m2 for five days) based chemotherapy, followed by haploidentical lymphocyte infusion (HLI) that was applied as induction therapy for elderly patients with AML. Furthermore, the role of HLI infusion was explored in a mouse model. The clinical trial included 29 elderly patients (median age: 64, range 57-77) with AML. Sixteen cases achieved complete remission (CR) and 9 cases achieved partial remission (PR) after the first treatment cycle. Of the patients with PR, 5 subjects achieved remission after the second induction, which brings the overall CR rate to 72.4%. The 2-year overall survival (OS) and disease-free survival (DFS) was 59.6% and 36.9% respectively. The treatment regimen was well tolerated with only one patient died of severe pneumonia one month after the first treatment. In the mouse experiment, we found that DAC/HLI significantly enhanced the survival of leukemic mice. These results suggested that DAC-based chemotherapy combined with HLI is an alternative first line induction therapy for elderly patients with AML. This trial is registered at ClinicalTrials.gov (NCT01690507).

Keywords: Induction therapy; acute myeloid leukemia; decitabine; haploidentical lymphocyte infusion.

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare that there is no conflict of interest.

Figures

Figure 1. Survival results

A. Overall survival and B. disease-free survival. Vertical marks reflect last follow-up times for censored observations.

Figure 2. Blood count recovery after induction therapy of DAC-based chemotherapy combined with haplo-identical donor lymphocytes

Box plots show the median (line), interquartile (box extents), and range (whiskers) of WBC A. and platelet count B. for all patients during the time of the induction therapy. Blood count data are summarized every second day.

Figure 3. DAC treatment induced autologous anti-leukemia response and acted in synergy with adoptive T cells transfusion

A. WEHI-3 cells were injected i.p. into Balb/c mice at 1×105 cells/mouse. DAC (0.5mg/kg/day for 5 days) and cytarabine (10mg/kg/d for 5 days) were administrated 5 days later. Lymphocyte from CBF1 mice were injected intravenously 48 hours later. Mouse survival was monitored every two or three days. Five to six mice were used in each group and data were pooled from two experiments. B. WEHI-3 cells were injected i.p. into Balb/c mice at 1×105 cells/mouse. DAC (1mg/kg/day for 3 days) or PBS were administrated 5 days later. Purified CD3+ cells were harvested from each mouse 7 days after the treatment for transfer. Meanwhile, in vitro DAC (0.25uM for 3 days) treated WEHI3 cells were injected into naïve Balb/c nude mice i.p. at 5×104 cells/mouse. Then harvested CD3+ cells were adoptively transferred intravenously into with/without WEHI3 nude mice at 2×107 cells/mouse. Mouse survival data is shown. Eight mice were included in each group and data shown are representative of two independent experiments.