Microtransplantation Improved Outcome in Elderly Acute Myeloid Leukemia Patients - Report from China Microtransplantation Cooperative Group
Authors: Guo Mei , Li Jianyong , Dong Zheng , Liu Li , Shen Xuliang , Zhan Xinrong , Wu Depei , Yang Linhua , Bao Yangyi , Lu Xuzhang , Yu Changlin , Qiao Jianhui , Hu Kaixun , SUN Wanjun , Zuo Hongli , Huang Yajing , Qiao Junxiao , CAI Bo , LIU Zhiqing , LIU Tieqiang , Yao Bo , Zhao Hongxia , WANG Juan , SUN Qiyun , Ai Huisheng 
Published: October 2019

Abstract
The acute myeloid leukemia in elderly patients (EAML) is always associated with low complete remission (CR) rate and a poor survival due to prolonged pancytopenia and resistance of leukemic blasts to chemotherapy. The standard or high dose induction chemotherapy improved CR rate but remission is usually transient. Nonmyeloablative allergenic stem cell transplantation shows some curative effects but associated with severe graft-versus-host disease (GVHD). Recently, our clinical studies showed that HLA-mismatched microtransplantation (MST) could increase CR rate and improve the survival but without GVHD. However, it is still lack of data and multicentre studies about MST in such patients. Here, we designed a multicentre study about microtransplantation in combination with chemotherapy in such patients and elevate effects and toxicity.
Method. Total of the 148 patients with AML at the age of 60 years or over from May 2005 to May 2014, were enrolled in this study from the 11 hematology disease centers in China. The diagnosed was defined by the French-American-British (FAB) and WHO criteria. Chromosomal and immunephenotyping analyses were performed by pre-treatment of bone marrow obtained. Patients with acute promyelocytic leukemia or with a blast crisis of chronic myeloid leukemia were excluded. High risk was defined by the presence of complex cytogenetic abnormalities (with 3 or more cytogenetic abnormalities), secondary AML, or a WBC count of 50,000/µL or above. Other patients were considered at a standard risk. In accordance with the Helsinki Declaration, written informed consent for enrollment in this study was obtained from the patients or their legal guardians and the donors. Induction therapy includes cytarabine and anthracycline followed by HLA-mismatched G-CSF Mobilization HLA-mismatched donor peripheral stem cells (G-PBSC) infusion. The patients who achieved complete remission (CR) further received two courses of cytarabine as post-remission chemotherapy. None of the patients received any GVHD prophylactic treatment and further maintenance therapy. The donor and recipient HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 alleles were genotyped using a PCR-SSP method. All of 148 patients had HLA-mismatched related or unrelated donors including 126 with a family-related donor, 16 with a distantly related donor and 6 with an unrelated donor.
G-PBSC infusion: the median number of mononuclear cells, CD34+ and CD3+ T cells infused per course was 2.9 (1.2-5.2)´108/kg, 1.7(1.1-4.6)´106/kg and 0.9(0.5-2.6)´108/kg, respectively.
Results. Total of 148 patients were divided into three groups with 60-65 years (n=54), 66-70 years (n=41) and over 71 years (n=53). The overall CR rate was 77% and CR rate of the first cycle of induction chemotherapy was 55.3%. The CR rate was not significantly different among the patients with 60-64 years (74.1%), 65-70 years (80.4%), and over 71 years (77.4%). The CR rate was much higher in the standard group than in the high risk group (88.2% vs. 63.3%, P=0.04). The early death rate and severe infection was no significantly different among three groups. The median recovery time of neutrophils and platelets was 12d and 14d, which were not significantly different among three groups. The probabilities of 12 months OS, 24 months and 36 months were not significantly different among the patients with 60-65 years (80.9%, 60.9% and 55.8%), 66-70 years (65.4%, 46.5% and 34.9%) and over 71 years (71.3%, 30.6% and 26.8%). No definite clinical acute or chronic GVHD was observed in all of the patients but two patients who developed a severe acute GVHD and dead on day 36. A frequencies of HLA-A0201/2402WT1+CD8+ T-cells was 0.23% which is no significantly difference between the patients with low 70 years or more. The donor micro-chimerism was detected in 11 of the 18 female patients with a range of 0.0000151- 0.0386 copies of gene expression.
In conclusion, the microtransplantation combined conventional chemotherapy can result in a higher CR rate and OS with a shorter duration of pancytopenia, lower severe infections and hardly no GVHD, suggested that it is a much safer and effective new therapy for elderly AML patients including those who over 70 years old.

Disclosures
No relevant conflicts of interest to declare.