Allo-Hematopoietic Stem Cell Transplant in China: 2014 Update

235 chapter 30 Allo-Hematopoietic Stem Cell Transplant in China: 2014 Update Meng Lv 1 and Xiao-jun Huang 1,2 1 Peking University People s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China; 2 Peking- Tsinghua Center for Life Sciences, Beijing, China Corresponding author: huangxiaojun@bjmu.edu.cn INTRODUCTION The history and status of allogeneic hematopoietic stem cell transplantation (allo- HSCT) in China between 1981-2011 was reviewed in 2012 (1). In the past two years, progress has been made in haploidentical HSCT (haplo-hsct), allo-hsct for aplastic anemia (AA), and in new strategies to overcome relapse and graft-versushost-disease (GVHD). This review focuses on the latest achievements in allo-hsct in China. According to data collected by the Chinese Hematopoietic Stem Cell Transplantation Registry Group from 60 active centers, Peking University People s Hospital performs 600 allo-hsct cases annually and approximately 12 centers perform 80-200 cases per year. The total number of HSCT cases in all 60 active centers increased steadily from 2,194 cases in 2012 to 2,879 cases in 2013. By the end of 2014, the total number of annual HSCT in all 60 centers has risen to greater than 3500. identical donors have become the predominant donor source for allo-hsct in China, as related haplo-hsct has been adopted as clinically routine in more than 30 main HSCT centers in China (1-4). Between 2008 and 2012, haplo-hsct accounted for 28.3%-32.9% of total allo-hsct cases, which was the second largest type after human leukocyte antigen (HLA) identical sibling cases (37.6%-47.7%). In contrast, between 2013 and June 2014, haploidentical donors took first place even compared with HLA identical sibling donors (haploidentical versus identical: 41.9% versus 37.4 %), other donor types including unrelated (17.1%), and umbilical cord blood (3.5%) (Fig. 1). The distribution of diseases leading to allo- HSCT between 2013 and June 2014 is as follows: acute myeloid leukemia (AML, 35.1%), acute lymphoblastic leukemia (ALL, 27.1%), AA (10.8%), myelodysplastic syndrome (MDS, 9.5%), chronic myeloid leukemia (CML, 6.6%), Mediterranean anemia (MIA, 4.6%), non-hodgkin s lymphoma (NHL, 3.2%), and other diseases (3.2%) (Fig. 2). Between 2013 and June 2014, the proportion of CML patients receiving allo-hsct gradually decreased due to the advantage of using tyrosinekinase inhibitors in the chronic CML phase (5). Conversely, new strategies during this time period have contributed to increasing allo-hsct numbers in AA patients (6). -HSCT There had long been a shortage of HLA matched sibling donors for HSCT in China (1). -HSCT with related family donors, especially the Beijing Model T-replete myeloblative haplo- HSCT developed by our groups, has proven to be a reliable source of stem cells for patients, as it provides comparable outcomes to matched sibling or unrelated donors while offering the benefits of rapid and nearly universal donor availability (7-9). Not only has the Beijing Model been widely applied in China, Di Bartolomeo et al. got promising Clinical Transplants 2014, Terasaki Foundation Laboratory, Los Angeles, California stem cell transplants in china 2014

236 lv and huang 2008-2012 2013-2014 Cord 4% Cord 4% Unrelated donor 20% HLA-identical sibling donor 45% Unrelated donor 17% HLA-identical sibling donor 37% 31% 42% Figure 1. Donor source for allo-hsct in China. MDS 9% CML 7% AA 11% MIA NHL 5% 3% others 3% ALL 27% AML 35% Figure 2. Distribution of diseases leading to HSCT, 2013-2014. results in Europe (10-12). It is anticipated that more than half of the haplo-hsct cases performed worldwide will eventually follow similar protocols to the Beijing Model (13). The success of haplo- HSCT can be attributed to: 1) the optimization of protocols, such as the anti-thymocyte globulin (ATG) dosage; 2) pre-transplant risk stratification, such as donor selection and risk scoring; and, 3) the therapeutic strength over chemotherapy. Over the years, ATG has been a critical component in the conditioning regimen of T-replete haplo-hsct, yet the optimal dose remains unknown. In a recent prospective, randomized trial (RCT, ChiCTR-TRC-11001761), our group demonstrated that a 6 mg/kg dose of ATG decreased the risk of Epstein-Barr virus reactivation and late-onset hemorrhagic cystitis. However, grade III IV acute GVHD (agvhd) was higher in the ATG 6 mg/kg dose group compared with the group receiving a 10 mg/kg dose of ATG (16.1% versus 4.5%) (14, 15). A new regimen total body irradiation (TBI)/ cyclophosphamide (Cy) plus ATG, which includes TBI (700 cgy)/cy (3.6 g/m 2 )/simustine (250 mg/m 2 ) plus ATG (10 mg/kg), is also feasible and has shown promise in T cell-replete haplo-hsct. In a study of ALL patients, TBI/Cy plus ATG promoted stable engraftment and a lower incidence of liver toxicity and hemorrhagic cystitis compared with busulfan (Bu)/Cy plus ATG (16). As the new era of everyone has a donor has come (17), there has been a shift from a shortage of donors to stratification based on donor selection factors. In selection of the best donor, matching HLA, which played a predominant role in unrelated transplants, has not been significantly correlated with transplant outcomes in haplo-hsct (18, 19). Therefore, we might focus on factors other than HLA to determine the impact on transplant outcomes. Based on a large sample size and relative consistency of transplant variables, Wang et al. propose an algorithm for donor selection other

237 than HLA (20). It was suggested that choosing young, male, non-inherited maternal antigenmismatched donors is reasonable. Transplants from older mothers and non-inherited paternal antigen-mismatched donors should probably be avoided. As R. Handgretinger commented, this algorithm will have a major impact on outcome for a large number of patients (13). Systematic, standardized pre-transplant risk stratification is an important tool for predicting patient outcomes following allo-hsct. The European Group for Blood and Marrow Transplantation (EBMT) risk score was found feasible to predict patient outcomes following haplo- HSCT. The haploidentical EBMT risk score, which uses number of HLA disparity instead of donor type, can also be used to predict patient outcomes in the Beijing Model (21). The predictive value of the HSCT-specific comorbidity index has also been established in haplo-hsct (22). Although the effects of HLA-matched allo-hsct on patients with acute leukemia in first complete remission (CR1) have been well established, there has been controversy as to whether haplo-hsct as post-remission treatment in patients has a favorable impact on survival compared to chemotherapy alone. In a recent prospective study including 419 patients with intermediate- or high-risk AML in CR1, it was revealed that haplo-hsct resulted in a lower cumulative incidence of relapse (12.0% versus 57.8%; p<0.0001) and superior survival [4-year disease-free survival (DFS): 73.1% versus 44.2%, p<0.0001; 4-year overall survival (OS): 77.5% versus 54.7%, p=0.001] compared with the chemotherapyalone group (23). Furthermore, comparable outcomes were observed among high- and low-risk Philadelphia chromosome-negative (Ph-negative) ALL CR1 patients after haplo-hsct. -related donors could be considered for adults with Phnegative ALL in CR1 as an important alternative donor source in cases when no identical sibling donor (ISD) is available. In a series of retrospective studies, patients with either high-risk or standard-risk ALL who underwent haplo-hsct had significantly improved 3-5 year OS/DFS and lower relapse rates, while the non-relapse mortality rate was not different between patients treated with haplo-hsct versus chemotherapy (24, 25). Comparable outcomes were observed among high- and low-risk Ph-negative ALL CR1 patients after haplo-hsct. Thus, haplo-hsct may be superior to chemotherapy alone as postremission treatment for most non-low-risk AML and ALL patients when an ISD is not available. The refinement of protocols and pre-transplant risk stratification has contributed to the vigorous development of haplo-hsct in China. Besides the Beijing Model, which has been verified both in Asian and Caucasian people, haplo-hsct could play a growing role in allo-hsct worldwide. Allo-HSCT for Aplastic Anemia It has been a half century since the first bone marrow transplant was performed in Asia in a 20 year old female patient with acquired severe AA (SAA) and who received a transplant from her syngeneic sister. Due to new strategies for allo- HSCT from ISD, unrelated donors (URD), and cord blood and haploidentical donors, the annual number of cases of allo-hsct for SAA in China has rapidly increased, from fewer than 60 cases (5.53% of all allo-hsct) in 2008 to more than 400 cases (12.02%) in 2014. Allo-HSCT for SAA from ISD is characterized by a combination of granulocyte colony stimulating factor mobilized bone marrow (BM, G-BM) plus peripheral blood (PB) harvest (G-PB) (26). It was suggested that T-cell hypo-responsiveness and polarization of T cells from Th1 to Th2 could be maintained after in vitro mixture of G-PB and G-BM (27). As an alternative source of stem cells in SAA, G-PB has historically been inferior to grafts of bone marrow origin. This is partially due to the higher risk of severe acute GVHD (agvhd) and chronic GVHD (cgvhd) (28). However, there has been a limited donor source available for G-BM grafts compared with G-PB in the China Marrow Donor Program. The latest multi-center studies from China and other Asian countries have revealed that G-PB resulted in less graft failure (18% versus 9.1%, p=0.013), similar grade II-IV agvhd, cgvhd, and comparable outcomes (89.7% versus stem cell transplants in china 2014

238 lv and huang Table 1. Cord blood allo-hematopoietic stem cell transplantation for severe aplastic anemia in China. Author Patients Condition Zou F, et al. JiNan Military Liu H, et al. An-Hui Li Y, et al. Guang-Dong Xie LN, et al. JiNan Military A+P N=25 A+P N=18 A+P N=16 P N=36 RIC CY+ATG GVHD Prophylaxis CsA 82.4%, p=0.665) with G-BM in pediatric patients with SAA (29). Whether adult patients could get similar results remains to be investigated. Although URD cord blood transplant (CBT) has not yet been recommended for SAA patients because of the high risk of graft failure (30), data from several Chinese teams indicates that CBT for SAA might facilitate autologous recovery and improve survival with a low risk of transplant-related mortality, regardless of the high risk of rejection (Table 1). These promising results merit further investigation and confirmation in a larger number of patients. -HSCT has been considered a potential third-line option in patients with SAA failing at least one course of immune suppressive therapy with ATG and in the absence of ISD or URD. Both the ex vivo T-cell-depleted and unmanipulated grafts have been used in the haploidentical setting. However, they have resulted in a 25% probability of graft failure at 100 days and 5-year OS less than 30% (31, 32). Based on the Beijing Model, haplo-hsct from unmanipulated grafts for SAA has improved. The conditioning regimen includes BU, CY and ATG combined with cyclosporine A, mycophenolate mofetil, and short-term methotrexate for GVHD prophylaxis. This regimen was first tried in 19 patients and led to 100% donor myeloid engraftment and a 5-year OS of 68.4% (6). In 2014, this cohort had reached more than 50 cases. The group had a 2-year probability of OS of 76% (unpublished data). Outside of this study, several allo-hsct centers in China have achieved similar results following the same or modified protocols (Table 2). Based Engraft No report RIC FLU+CY+ATG CsA+MMF +1m 5.5% +3m 0% CY+ATG RIC CY+ATG CsA+MMF 6.3% CsA No report Complete Remission 3-year 88% 6-month 81% 1-year 65% 6-month 51% OS 3-year 92% 2-year 88.9% 2-year 94% 3-year 83% Publication J Hematol Oncol 2011 (50) Bone Marrow Transplant 2012 (51) Eur J Hematol 2013 (52) Cell Immunol 2014 (53) Abbreviations: A adult; ATG - anti-thymocyte globulin; CsA cyclosporine A; CY cyclophosphamide; FLU fludarabine; GVHD graft-versus-host-disease; MMF mycophenolate mofetil; OS overall survival; P pediatric; RIC reduced intensity conditioning; standard regimen. on these promising experiences, haplo-hsct had been promoted to second-line therapy in AA Guidelines of APHCON (33). Furthermore, a multicenter, prospective study (ChiCTR-ONC-12002107) was initiated by uniform protocols following the Beijing Model in June 2012. By the end of 2014, nearly one hundred patients had been enrolled. This prospective clinical trial would provide further evidence to evaluate the effectiveness of haplo- HSCT in the management of SAA. Allo-HSCT has played an increasingly predominant role in the treatment of SAA in China. These novel protocols might also contribute to the refinement of certain international guidelines. Pre- and Post-Transplant Risk Stratified Intervention For Relapse Relapse remains the most devastating enemy after allo-hsct and accounts for nearly half of post allo-hsct deaths. Recent advances in biomarkers have enabled us to predict the risk of relapse by dynamically monitoring the minimal residual disease (MRD) before or after allo-hsct. Pre- and post-transplant risk stratified intervention triggers a more potent graft-versus-tumor effect without increasing the treatment associated mortality. Therefore, reliable biomarkers, powerful intervention strategies, and the art of combining these together would be keys to fight relapse. Although AML with t(8;21) generally has a favorable prognosis, it is known that relapse occurs in 40% of cases and long-term survival is poor. Therefore, early identification of patients at high-

239 Table 2. -hematopoietic stem cell transplantation for severe aplastic anemia in China. Author Center Xu LP, et al. Peking U. Wang H, et al. Air-Force Gao L, et al. Chong-Qing Wu Y, et al. Chinese PLA General Wang Z, et al. Air-Force Patients A N=19 A+P N=22 A N=26 A+P N=21 P N=17 Condition BU+CY+ ATG BU+CY+ FLU+ATG CY+FLU+ ATG CY+FLU+ ATG / Bu+ATG BU+CY+ FLU+ATG Donor Grafts BM+PB BM+PB+MSC BM+PB BM+PB+MSC BM+PB risk of relapse following chemotherapy is valuable and can help in determining the need for allo-hsct as post-remission therapy. It was revealed in AML05 multicenter trial (ChiCTR-OCH-12002406) that MRD status after the second consolidation rather than induction or first consolidation could discriminate patients at high-risk of relapse. Allo- HSCT could reduce relapse and improve survival compared with chemotherapy for these high-risk patients (cumulative incidence of relapse, HSCT versus chemotherapy: 22.1% versus 78.9%, p<0.0001). MRD-directed pre-transplant risk stratification may improve the outcome of t(8;21) AML in CR1 (34). Furthermore, in high-risk patients who received allo-hsct, monitoring MRD within 3 months after HSCT, rather than identifying c-kit mutations, was an independent factor for cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) (p=0.001). The 2-year CIR and LFS for patients with or without donor lymphocyte infusion were 24% versus 87% (p<0.001) and 64% versus 0%, respectively (p<0.001), which provides supporting evidence for post-transplant risk-directed preemptive therapy (20). In contrast to the dynamic cutoff values in MRD monitoring of t(8;21) AML, detectable MLL gene expression at any level (MLL > 0%) was associated with a higher rate of relapse (hazard ratio, HR 18.643; p=0.001), GVHD Prophylaxis Engraft GVHD incidence CsA+MTX+ MMF CsA+MTX+ MMF +/- CD25 CsA+MTX+ MMF CsA+MMF+ CD25 CsA+MTX+ MMF 100% 100% 92.3% 100% 100% a II-IV 42.1% c 56.2% a II-IV 4.5%; c 0% a II-IV 12.0%; c 40% a II-IV 42.8%; c 50% a II-IV 30.5%; c 21.25% OS 5-year 68.4% Publication Bone Marrow Transplant 2012 (6) 2-year 88.9% Cytotherapy 2013 (54) 3-year 84.6% 2-year 74.1% 1-year 71.6% Bone Marrow Transplant 2014 (55) Stem Cell Res 2014 (56) Bone Marrow Transplant 2014 (57) Abbreviations: a acute; A adult; ATG anti-thymocyte globulin; BM bone marrow; BU busulfan; c chronic CsA cyclosporine A; CY cyclophosphamide; FLU fludarabine; GVHD graft-versus-host-disease; MMF mycophenolate mofetil; MSC mesenchymal cells; MTX methotrexate; OS overall survival; P pediatric; PB peripheral blood; RIC reduced intensity conditioning; standard regimen. lower LFS (HR 7.267; p =0.002), and lower OS (HR 8.259; p =0.002) in MLL+ AML after allo-hsct (35). In addition to these well-known fusion genes, new biomarkers have been translated from Bench to Bedside. In the non-obese diabetic/severe combined immunodeficient xenograft assay, it was found that CD34+CD38-CD58-cells are leukemiapropagating cells (LPCs) of Ph+ ALL (36). Based on the original blast phenotypes at diagnosis, presence of CD34+CD38 CD58 LPCs are directly correlated with a higher 3-year CIR and worse LFS/OS after allo-hsct (37). Prophylaxis or maintenance therapy based on this pre-transplant risk-stratification remains to be explored in the near future. Chimerism analysis monitors of hematopoietic cells from donor and recipient origin after allo- HSCT is an important tool for the surveillance of post-transplant engraftment and offers the possibility of identifying impending graft rejection and recurrence of underlying leukemia. Semiquantitative polymerase chain reaction (PCR) for detecting autologous cells at a cutoff of 1% was used to discriminate complete chimerism (CC) and mixed chimerism (MC) in a PB or BM sample. It was found that MC patients without intervention had inferior progression free survival compared with CC (80% versus 30%, p<0.001) (38). Very recently, quantitative chimerism using real time quantitative stem cell transplants in china 2014

240 lv and huang PCR based on 29 sequence polymorphisms indicated a higher probability of relapse, with 100.0% sensitivity and 79.6% specificity at a cutoff point of 1.0% (2-year relapse rate 55% versus 0%), which was also associated with inferior LFS and OS (39). Therefore, by integrating pre- and posttransplant risk stratification, we might choose the right intervention at the right time for the right patients, which would help to further decrease the incidence and threat of relapse. Prophylaxis and Management of Graft-Versus-Host-Disease GVHD is one of the main complications post- HSCT. Considering the high proportion of haplo- HSCT cases, novel strategies to prevent GVHD are urgently needed. Due to the success of the combination of cyclosporine A, methotrexate, and mycophenolate mofetil as GVHD prophylaxis in previous study (40), the Chinese Bone Marrow Transplant Cooperative Group initiated a prospective, single arm phase II open-label, multi-center clinical trial. Five hundred eight patients were enrolled and this novel GVHD regimen decreased the risk for agvhd by 42% without improving the risk for cgvhd compared to historical controls (41). Cellular components of grafts provided alarming information for the onset of GVHD. It was revealed that patients who received a higher number of Th17 cells in their allografts had higher incidences of agvhd and cgvhd compared with patients who received a lower number of Th17 cells (42, 43). On the contrary, cell dosage of monocytic and promyelocytic myeloid-derived suppressor cells might protect patients from occurrence of GVHD (44). Based on the progress in predicting GVHD, a total of 228 patients were enrolled in a prospective, randomized, controlled, clinical trial (NCT01607580), and stratified as high-risk and lowrisk arms according to risk-stratification. Patients of the high-risk arms were randomly assigned in a 1:1 ratio to the low-dose glucocorticoid prophylaxis group and the control group. The cumulative incidence of grade II-IV agvhd on day 100 was 20.9%±4.8% in Group A, which was comparable to Group C (25.5%±4.8%, p=0.430), both of which were significantly lower than that of Group B (48.1%±5.9%, p<0.001). Risk-stratification directed prophylaxis for GVHD with the addition of low-dose of corticosteroids could significantly decrease the incidence of and delay the onset of grade II-IV agvhd without increasing infections and delaying immune recovery (45). Immune recovery or immune reconstitution have the greatest impact on GVHD after allo-hsct. Immune modulatory strategies by cells, interleukin factors, provide great intervention to prevent GVHD. Mesenchymal stromal cells (MSCs) have shown promise in treating refractory cgvhd. It was found that MSCs could promote the survival and proliferation of CD5+ regulatory B cells (Bregs), and that indoleamine 2, 3-dioxygenase partially participates in the MSC-mediated effects on Breg cells. Thus, CD5+ Breg cells may have an important role in the process of MSC-induced amelioration of refractory cgvhd and may provide new clues to reveal novel strategies (46). In animal models, it was indicated that IL-35 overexpression could suppresses CD4+ effector T-cell activation, leading to a reduction in alloreactive T-cell responses and agvhd severity. Furthermore, IL-35 overexpression results in a selective decrease in the frequency of Th1 cells and an increase of IL-10-producing CD4+ T cells in agvhd target tissues (47). In clinic, Zhang XH, et al. revealed that the PB of patients with grades III-IV agvhd (23.46 ng/ml) had reduced IL-35 compared to transplanted patients with grades I-II agvhd (40.26 ng/ml, p < 0.01) or patients without agvhd (41.40 ng/ml, p < 0.05). The patients who received lower levels of IL-35 cells in the G-BM (28.0 ng/ml, p = 0.551) or lower levels of IL-35 in PB progenitor cells (53.46 ng/ml, p = 0.03) exhibited a higher incidence of agvhd. Patients with agvhd have increased platelet aggregation, while IL-35 may affect the development of agvhd by inhibiting platelet activation and aggregation (48). Besides IL-35, in a prospective randomized control trial of low dose interleukin-2 (IL2) treatment post allo- HSCT (NCT01517347), standard risk leukemia

241 patients following day 60 post-transplantation were randomly assigned in a 1:1 ratio into the treated group or the control group. The treated group received IL2 treatment every 14 days for 4 to 6 courses in the absence of disease progression or unacceptable toxicity. It was found that low doses of IL2 could expand CD4+CD25highCD127-/lowT regulatory cells and natural killer (NK) cells and prevent cgvhd. Meanwhile, cytotoxicity of NK cells in the IL2 group was significantly higher than in the control group during the IL2 treatment period. IL2 therapy has no effect on reconstitution of the absolute number of CD3+T cells, CD4+ T cells, CD8+ T cells, or the reconstitution of conventional T cells, Th1 cells, or Th17 cells (49). CONCLUSION Substantial progress in the fields of haplo-hsct and allo-hsct for AA as well as new strategies to overcome relapse and GVHD have been made during the last 2 years in China and have contributed to the worldwide progress of allo-hsct. Allogeneic hematopoietic stem cell transplantation (allo-hsct) provides powerful curative weapons for patients with certain hematological diseases. Great improvements have been made within recent years, particularly SUMMARY In the near future, there will be more opportunities for cooperation between China and the western world. Take donor selections for haplo-hsct for an example: as a common principle and mechanism of donor selection remains to be elucidated, it would be of great interest to verify the proposed algorithm of the Beijing Model in other haplo approaches, especially T cell-depleted transplant in Europe and high-dose cyclophosphamide T-replete models in the United States. If there are some universal principles across these haplo transplant models, what is behind these phenomena? Would it be the critical point to cross the HLA barriers? If there are more disparities rather than common principles, what is the underlying mechanism of tolerance induction and anti-leukemia effects in specific models? Acknowledgement This article was supported by the National Natural Science Foundation of China (grant no. 81230013, 81400146). Beijing Municipal Science and Technology Program (grant no. Z141100000214011). in the fields of haploidentical HSCT, allo-hsct for aplastic anemia, and strategies to overcome relapse and graft-versus-host-disease. This review will update the current state of allo-hsct in China. stem cell transplants in china 2014 1. Lv M, Huang XJ. Allogeneic hematopoietic stem cell transplantation in China: where we are and where to go. J Hematol Oncol 2012; 5:10. 2. Luo Y, Xiao H, Lai X, et al. T-cell-replete haploidentical HSCT with low-dose anti-t-lymphocyte globulin compared with matched sibling HSCT and unrelated HSCT. Blood 2014; 124:2735. 3. Chang YJ, Huang XJ. identical hematopoietic stem cell transplantation with unmanipulated granulocyte colony stimulating factor mobilized marrow and blood grafts. Curr Opin Hematol 2012; 19:454. REFERENCES 4. Piemontese S, Ciceri F, Labopin M, et al. A survey on unmanipulated haploidentical hematopoietic stem cell transplantation in adults with acute leukemia. Leukemia 2014, in press. 5. Jiang Q, Xu LP, Liu DH, et al. Imatinib results in better outcomes than HLA-identical sibling transplants in young persons with newly diagnosed chronicphase chronic myelogenous leukemia. Leukemia 2013; 27:2410.

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