Haploidentical stem cell transplantation: anti-thymocyte globulin-based experience

doi:10.1053/j.seminhematol.2016.01.004

Seminars in Hematology

Volume 53, Issue 2, April 2016, Pages 82-89

https://doi.org/10.1053/j.seminhematol.2016.01.004 Get rights and content

Abstract

Haploidentical stem cell transplantation (haplo-SCT) with an anti-thymocyte globulin (ATG) preparative regimen is associated with induced immune tolerance, rapid hematopoietic recovery, effective prevention of graft-versus-host disease (GVHD), and lower non-relapse mortality (NRM). This has become a common and successfully applied protocol in patients with hematological diseases undergoing haplo-SCT. Survival rates among patients who undergo unmanipulated haploidentical blood and marrow transplantation (HBMT) with anti-thymocyte globulin (ATG)-based regimens are comparable to those following human leukocyte antigen (HLA)-matched sibling transplantation or unrelated donor transplantation. Unmanipulated HBMT can also be successfully used as a post-remission treatment algorithm for acute lymphoblastic leukemia (ALL) and adult acute myeloid leukemia (AML) in cases with unfavorable cytogenetics. Future investigations should focus on further improving donor selection, optimizing allografts, dealing with primary graft failure, and relapse prophylaxis and treatment.

Introduction

Successful establishment of multiple haploidentical stem cell transplantation (haplo-SCT) protocols with promising outcomes—including T-cell–replete (TCR) and T-cell–depleted (TCD) transplants—provides alternative treatment options for patients lacking human-leukocyte antigen (HLA)-matched related or unrelated donors [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23] Stem cells from haploidentical donors have the advantages of widespread availability and ease of procurement, and the shift from TCD grafts to unmanipulated marrow and/or peripheral blood stem cells has made haplo-SCT easier to perform [2], [7], [24], [25].

We previously established a protocol for unmanipulated haploidentical blood and marrow transplantation (HBMT) based on immune tolerance induction using granulocyte colony-stimulating factor (G-CSF) and anti-thymocyte globulin (ATG) [26], [27], which shows promising results [2], [7], [28], [29]. Over the last decade, a series of studies from Peking University demonstrated that unmanipulated HBMT can lead to rapid immune recovery [30], [31], desirable health-related quality of life [32], and a survival rate comparable to that following HLA-matched sibling transplantation (MSDT) or unrelated donor transplantation (MUDT) [1], [16], [17], [30]. Furthermore, the HBMT protocol is superior to umbilical cord blood transplantation for treating pediatric hematological malignancies [33]. HBMT can also be successfully used as a post-remission treatment algorithm for acute lymphoblastic leukemia (ALL) and adult acute myeloid leukemia (AML) in cases with unfavorable cytogenetics [5], [6], [7].

Several ATG preparative-based haplo-SCT modalities have recently been established, and have become widely used in China and applied in a number of centers in Asia and Europe (Table 1) [4], [13], [15], [16], [17], [18], [19], [20], [21], [24], [25], [34], [35], [36], [37], [38], [39], [40]. The present review focuses on recent advances in haplo-SCT with ATG. The improvements are mainly discussed with regards to conditioning regimens, allograft choice, and prophylaxis of graft-versus-host disease (GVHD). We also review the results of prospective comparisons of ATG-based haplo-SCT protocols with MSDT and MUDT. Finally, we discuss future directions, which should focus on selecting the best donor, optimizing allografts, dealing with primary graft failure, and relapse prophylaxis and treatment.

Section snippets

Transplant outcomes after haplo-SCT with ATG-based regimens

The clinical outcomes of haplo-SCT with ATG-based regimens have been previously reviewed by our group and others [8], [9], [41]. Table 1 summarizes the recent reported clinical outcomes of this haploidentical protocol [4], [16], [17], [18], [19], [20], [23], [24]. The Peking University Group reported data following unmanipulated HBMT in 1,210 subjects over the last 10 years, including the 3-year cumulative incidences of transplant-related mortality (TRM; 17%), relapse (17%), disease-free

Prospective cmparisons of haplo-SCT with an ATG-based regimen versus other modalities

Clinical outcomes of haplo-SCT have been comparable to those of MSDT and MUDT, as reported in retrospective studies [16], [17], [33], [34], [47] and reviewed by our group [8], [9] and others [48]. Researchers from Zhejiang University, China prospectively compared the clinical outcomes of 305 patients with hematological malignancies who underwent MSDT (n = 90), MUDT (n = 16), and haplo-SCT (n = 99) [4]. They found that haplo-SCT was associated with higher incidences of grade II–IV GVHD (42.4%),

Strategies to improve transplant outcomes

To further improve transplant outcomes, more information is needed regarding these procedures. Here, we discuss recent progress, including best donor, conditioning regimens, stem cell source, graft failure and poor graft function, and donor lymphocyte infusion (DLI), in the field of haplo-SCT with ATG preparative regimens.

Conclusions

In summary, based on the data from original publications and from reviews on haplo-SCT with ATG-based regimens, we can draw the following conclusions. Several protocols for haplo-SCT with ATG-based regimens have been established, differing in the design of the conditioning regimens, the variety of allografts, and GVHD prophylaxis (Table 1, Table 2) [2], [4], [5], [17], [20], [21], [24], [25], [34], [37], [38], [39], [40], [43], [44], [46], [58], [79], [80]. Haplo-SCT with an ATG-based regimen

Future directions

To date, haplo-SCT with an ATG-based regimen has proven to be easily performed and highly effective, and has become one of the most commonly applied modalities in haploidentical transplant settings. Several strategies have been successfully applied during the transplantation process to improve transplant outcomes—including donor selection, improvements of the conditioning regimen and GVHD prophylaxis, and relapse prevention and treatment. For example, data from our group and others [72], [81]

Conflicts of interest

The authors declare no competing financial interests.

Acknowledgments

This work was supported in part by the National High Technology Research and Development Program of China (Program 863) (Grant No. 2013AA020401), the Milstein Medical Asian American Partnership Foundation, The Key Program of National Natural Science Foundation of China (Grant No. 81230013), the Scientific Research Foundation for Capital Medicine Development (Grant No. 2011-4022-08), and the National Natural Science Foundation of China (Grant No. 30971292).