Clinical Study of Allo-HSCT with Conditioning Regimen Containing Decitabine in the Treatment of advanced Acute Myloid Leukemia and Myelodysplastic Syndrom

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 hematologic malignancies can not achieve remission before transplantation. And the relapse rate of these patients after transplantation remains high obviously. Therefore, it is necessary to design a safe and effective conditioning regimen to improve the remission rate of these patients and disease-free survival (DFS), but to reduce transplantation related mortality (TRM). The optimal conditioning regimen not only can reduce tumor burden and eradicate minimal residual disease but also can make immunosuppressive state to ensure engraftment. As well as, it does not increase the TRM. One of the promising drugs of epigenetics is decitabine (DAC), which has a significant effect on a variety of hematologic malignancies. It is widely used in myelodysplastic syndromes(MDS) even for relapsed and refractory acute myelocytic leukaemia (AML). Because 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）.

Aims: This clinical study will investigate the security and efficacy of conditioning regimen containing decitabine. Further to explore the role in advanced malignant hematologic disease.

Methods: We retrospectively studied 20 cases of patients with hematologic malignancies, who underwent allo-HSCT with decitabine combined with conditioning regimens in the Department of Hematology, the First Affiliated Hospital of Soochow University during May 1, 2012 to April 30, 2014.

Results: 19 patients achieved complete remission and hematopoietic reconstitution after transplantation. Only 1 NR case died on day +27 post transplant. The median time of neutrophil and platelet reconstitution were 12 (10-22) and 14.5 (12-35) days respectively. The median time of archiving full donor chimerism [short tandem repeat (STR)STR>95%] was 18(13-62) days. The median follow-up post transplant was 246 (19-582) days. 3 cases relapsed. 2 cases were dead due to relapse.1 case achieved complete remission again after donor lymphocyte infusion (DLI). 1 CR case was dead due to hemorrhage of digestive tract. The other 15 CR cases were survival with continued remission. The estimated 2-year overall survival (2yr-OS) rate was 78%.The 2 year disease-free survival (2yr-DFS) rate was 62.6%. The cumulative relapse rate was 26.7%. The transplantation-related mortality (TRM) rate was 0. Furthermore, the estimated 2-yr OS and DFS of patients with DNMT3A mutations or abnormalities of chromosome 7 and complex chromosomal karyotype were 72.9% and 60.6% respectively. Concerning about transplant related toxicity, except one case has grade III gastrointestinal toxicity, all the other toxicities were mild (grade I-II). The cumulative rate of aGVHD and cGVHD were 20.5% and 48.3%.And the cumulative rate of aGVHD for grade I-II and grade II-IV were 15% and 10.5%.

Conclusions

1. Allo-HSCT is an effective treatment for refractory and relapsed AML and high- risk MDS. It is feasible to use conditioning regimen containing decitabine before allo-HSCT. The treatment were well tolerated.

2. 92.3% of the patiants achieved CR, and were well engraftment. Because of decitabine can promote megakaryocytic maturation and accelerate the release of platelet, so hematopoietic was reconstructed rapidly, especially for the megakaryocyte. The 2yr-DFS rate was 62.6%, the cumulative relapse rate was 26.7%. The conditioning regimen containing decitabine before allo-HSCT seems to reduce the incidence of aGVHD.

The prognosis and survival of the patients with complex chromosomal karyotype or chromosome 7 abnormalities or DNMT3A mutation may be improved by treating with decitabine containing conditioning regimen.