Stem Cell Research (2013) 12, 132–138

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Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells for severe aplastic anemia: Successful engraftment and mild GVHD Wu Yamei a,1 , Cao Yongbin a,1 , Li Xiaohong a , Xu Lixin a , Wang Zhihong a , Liu Pei a , Yan Pei a , Liu Zhouyang a , Wang Jing a , Jiang Shuang a , Wu Xiaoxiong a,⁎, Gao Chunji b , Da Wanming b , Han Zhongchao c a

Department of Hematology, The First Affiliated Hospital, Chinese PLA General Hospital, Beijing 100048, China Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China c TEDA Research Center of Life Science and Technology, State Key Laboratory of Experimental Hematology, Institute of Hematology, Tianjin 300020, China b

Received 24 March 2012; received in revised form 26 September 2013; accepted 1 October 2013

Abstract Haploidentical hematopoietic stem-cell transplantation (haplo-HSCT) is associated with an increased risk of graft failure and severe graft-versus-host disease (GVHD). Mesenchymal stromal cells (MSCs) have been shown to support in vivo normal hematopoiesis and to display potent immunesuppressive effects. We cotransplanted the culture-expanded third-party donor-derived umbilical cord MSCs (UC-MSCs) in 21 young people with severe aplastic anemia (SAA) undergoing haplo-HSCT without T-cell-depleted. We observed that all patients had sustained hematopoietic engraftment without any adverse UC-MSC infusion-related events. Furthermore, we did not observe any increase in severe aGVHD. These data suggest that UC-MSCs, possibly thanks to their potent immunosuppressive effect on allo-reactive host T lymphocytes escaping the preparative regimen, reduce the risk of graft failure and severe GVHD in haplo-HSCT. © 2013 Elsevier B.V. All rights reserved.

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapeutic modality for young patients with severe aplastic anemia (SAA) who have an immediate HLAidentical donor. However, less than 30% of patients who ⁎ Corresponding author at: Department of Hematology, The First Affiliated Hospital, Chinese PLA General Hospital, 51 FuCheng Road, Beijing 100048, China. Fax: + 86 10 66848181. E-mail address: [email protected] (X. Wu). 1 Wu Yamei and Cao Yongbin contributed equally to this study and should be considered as co-first authors. 1873-5061/$ - see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.scr.2013.10.001

require allogeneic HSCT have a human leukocyte antigen (HLA)-compatible sibling. In China, searching for HLA-matched donors is usually unsuccessful because no siblings are available for almost all young people. Fortunately, haplo-identical hematopoietic stem cell transplantation (haplo-HSCT) has come into clinical use to treat hematologic malignancies and the protocols have been greatly improved during the last decade (Guo et al., 2009; Lazarus et al., 2005). However, the results of haplo-HSCT in patients with SAA have been disappointing, due to high risk of treatment-related mortality (TRM) because of infection, bleeding, regimen-related toxicity,

Cotransplantation for severe aplastic anemia engraftment failure, and acute and chronic graft-versus-host disease (aGVHD, cGVHD) (Woodard et al., 2004; Lazarus and Koc, 2001; Tsutsumi et al., 2004; Tabbara et al., 2002). Mesenchymal stem cells (MSCs) are a heterogeneous subset of multipotent stromal stem cells, which express low levels of class I, but not class II, histocompatibility antigens and are not immunogenic in in vitro assays or preclinical models (Le Blanc et al., 2008; D.P. Lu et al., 2006; L.L. Lu et al., 2006). MSCs have also been shown to suppress primary and ongoing mixed lymphocyte reactions (Klyushnenkova et al., 1998; Di Nicola et al., 2002; Ball et al., 2007). MSCs can be isolated from many adult tissues, including bone marrow (BM), periosteum, adipose tissue, fetal liver, cord blood and umbilical cord (UC) tissues (In't Anker et al., 2003; Lee et al., 2004; Romanov et al., 2003). Recently, some experimental and clinical data demonstrated that BM-MSCs can support hematopoiesis, enhance the engraftment of HSCs, and reduce the incidence of GVHD following HSCT (Guo et al., 2009; Lazarus et al., 2005). However, the aspiration of BM involves invasive procedures, and the frequency and differentiation potential of BM-MSCs decrease significantly with age (D.P. Lu et al., 2006; L.L. Lu et al., 2006). Lu LL et al. have shown that a large number of MSCs can be easily isolated from the UC and collected using an accessible and painless procedure (D.P. Lu et al., 2006; L.L. Lu et al., 2006). Our recent data demonstrated that the modified haplo-HSCT combined with third-party donor-derived UC-MSCs for 50 patients with refractory/relapsed hematologic malignancy was not only safe and feasible but also effective for the improvement of donor engraftment and the reducing of severe GVHD (Wu et al., 2013). However, it is still unknown whether cotransplantation of UC-MSCs in haplo-HSCT recipients with SAA can reduce graft failure. Herein, we report the results of our clinical trial of haploHSCT with modified conditioning that was designed primarily to examine the safety and feasibility of the cotransplantation of culture-expanded third-party donor-derived UC-MSCs and donor HSCs in SAA patients. We further investigated the rates and kinetics of hematopoietic engraftment and the incidence and severity of GVHD.

Results Engraftment and chimerisms In Table 1, the median hematopoietic cell doses infused were 9.28 × 108 mononuclear cells (range, 6.30–13.18 × 108/kg) and 3.79 × 106 CD34+ cells (range, 1.96–10.20 × 106/kg). Data for all patients who survived at least 30 days after transplantation and were evaluable for engraftment are summarized in Table 2. Overall, the median time to achieve neutrophil engraftment (absolute neutrophil count ≥ 0.50 × 109/L) was 12.0 days (range, 8.0–21.0 days). Overall, the median time to achieve platelet engraftment ≥ 20 × 109/L was 14.0 days (range, 10.0–23.0 days). Delayed platelet recovery (N 30 days) was not observed in any of the 21 patients. All patients achieved full donor chimerism (FDC) (Table 2).

GVHD Table 2 indicates the incidence and severity of GVHD. Overall, 12 of 21(57.1%) patients experienced aGVHD between 20 and

133 78 days after transplantation, including 3 (14.3%) with grade I, 4(19.0%) with grade II, 4 (19.0%) with grade III and 1 (4.8%) with grade IV aGVHD. The other 9 patients had no aGVHD. Ten of 20 (50.0%) evaluable patients who survived at least 90 days after transplantation experienced cGVHD; cGVHD was limited in 7 patients (35.0%) and extensive in 3 patients (15.0%).

Survival Upon follow-up for 2.5 to 78 months, 17 of the 21 (80.9%) patients were alive. As shown in Fig. 1, the probabilities of 2-year disease-/progression-free survival were 74.1% in the 21 patients. No patients experienced disease relapse or progression. Four patients died; three patients died as a result of infection, and the other patients died as a result of GVHD.

Clinical safety outcomes As anticipated for the HSC transplant recipients, all 21 patients experienced at least 1 adverse event during the study period, and 16 of 21 (76.2%) patients developed at least one grade IV adverse event (Table 3). Only 4 patients (19.0%) demonstrated adverse events that were considered treatment related, such as GVHD, organ failure, or others (i.e., possibly, probably, or definitely). However, no patients experienced infusional toxicity during the UC-MSC infusion.

Discussion Graft failure and rejection for patients with acquired SAA remains as one of the important and life-threatening complications, especially in haplo-HSCT (Wagner et al., 1996; Passweg et al., 2006). The EBMT showed that for patients receiving HLA-identical sibling grafts, the rate of graft failure was more than 10% before 2000 (Bacigalupo et al., 2000). Over several decades, various transplant strategies have been introduced to decrease graft failure, with mixed success (Wang et al., 2009; Fang et al., 2008, 2009; Wagner et al., 1996; Passweg et al., 2006; Storb et al., 1986; DE Medeiros et al., 2001). In this study, all patients with SAA received 1 of 2 study-specified modified conditioning regimens without T-cell depletion for HLA-haplo relative HSCT. All patients with 2–3 mismatched loci achieved sustained full donor engraftment and prompt hematopoietic recovery. Results suggested that the modified conditioning regimen without high-dose immunosuppressive agents was sufficient to achieve sustained donor engraftment in which the third-party donor-derived UC-MSCs may play an important role. In allogeneic stem cell transplantation, MSC may be used for GVHD prophylaxis and treatment of severe aGVHD (Wang et al., 2009; Fang et al., 2008, 2009; Le Blanc et al., 2004; Lazarus and Koc, 2001). Le Blanc demonstrated that the infusion of MSCs was an effective therapy for patients with steroid-resistant GVHD in a phase II clinical trial (Le Blanc et al., 2008). Lu et al. showed that UC-MSCs do not express the immune costimulatory molecules or HLA-DR and express low levels of HLA-ABC (D.P. Lu et al., 2006; L.L. Lu et al., 2006). In our center, the results of haplo-HSCT were very disappointed from January 2006 to December 2007. Five patients aged 14 to 25 with 1–2 mismatched loci received haplo-HSCT with the same conditioning regimen and GVHD prophylaxis except

134 Table 1

Y. Wu et al. Demographic and transplant characteristics of patients and donors.

Case

Sex/Age

Status prior to Co-transplantation

Donor/Age

HLA mismatch

ABO pairs D/R

MNC 108/kg

Cd34 + 106/kg

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

M/29 M/18 M/19 F/23 F/12 M/13 M/16 M/4 M/24 F/23 F/12 F/15 F/25 F/15 M/16 F/19 M/21 M/13 M/23 F/31 F/9

VSAA ⁎ VSAA a,g,⁎ VSAA c,f,⁎ VSAA d,f,⁎ VSAA e,⁎ VSAA b,g,⁎ SAA & PNH g,# VSAA ⁎ VSAA c,⁎ SAA a,b,g,⁎ SAA g,⁎ SAA f,⁎ VSAA ⁎ VSAA ⁎

Brother/22 Father/44 Sister/23 Sister/18 Sister/16 Father/40 Mother/42 Mother/30 Mother/48 Mother/48 Mother/35 Sister/27 Mother/48 Father/44 Father/43 Brother/21 Father/41 Mother/34 Mother/51 Mother/57 Mother/32

A B DR B DR AB A DR A B DR A B DR AB A B DR A B DR A B DR A B DR B DR A B DR A B DR A B DR A DR B DR A B DR AB A B DR B DR

A/A A/A B/O O/A A/B O/O O/O AB/B A/AB B/AB O/O B/B A/A B/B AB/A B/O O/A A/A B/B O/O A/A

6.65 8.80 9.28 9.66 8.85 7.74 10.20 10.20 8.06 8.44 9.96 6.30 9.85 13.18 8.82 10.56 10.06 10.97 7.90 8.58 9.62

2.45 6.60 5.88 6.94 3.92 7.52 4.84 3.10 3.45 1.96 10.20 3.75 3.20 7.96 3.25 4.55 3.79 3.47 2.97 3.11 4.71

SAA g,⁎ VSAA ⁎ SAA g,⁎ VSAA ⁎ SAA b,g,⁎ SAA & PNH g,# SAA f,⁎

MNC, mononuclear cells; F, female; M, male; HLA, human leukocyte antigen; SAA, severe aplastic anemia; VSAA, very severe aplastic anemia; PNH, paroxysmal nocturnal hemoglobinuria; ATG, rabbit anti-human T-lymphocyte immunoglobulin; D, donor; R, recipient. a First graft failure. b Relapse after ATG. c Viral hepatitis before aplastic anemia. d Thyroid carcinoma before aplastic anemia. e Viral encephalitis before aplastic anemia. f More than 15 units red blood cells were transfused. g More than 25 units red blood cells were transfused. ⁎ Conditioning regimen 1. # Conditioning regimen 2.

UC-MSCs. Even though no patient had graft failure, one patient had mixed chimerisms (MC). The incidences for grades II to IV and III/IV aGVHD were up to 60.0% and 40%, respectively. At the same time, extensive cGVHD occurred in 1 patient (33.3%) of 3 evaluable patients who survived at least 90 days after transplantation. The most disappointing results were that only 2 (40.0%) patients were alive in the following 24 months. In the present trial, we intended for GVHD prophylaxis to consist of cyclosporine (CsA), mycophenolate mofetil (MMF), rabbit anti-human T-lymphocyte immunoglobulin (ATG), anti-CD25 antibody (CD25Ab) and UC-MSCs, and we did not observe an increase in severe aGVHD. Many studies have shown that the incidences for grades II to IV and III/IV aGVHD range from 44% to 64% and from 12% to 26%, respectively. Extensive cGVHD rates range from 30% to 46% (Bensinger et al., 2001; Couban et al., 2002). Grade III/IV aGVHD rates (23.8%) and cGVHD (47.6%) rates identified in the trial fall within these ranges and would be a little better than the above mentioned. Similar results were also observed in our recent studies in 50 patients with refractory/relapsed hematologic malignancy of haploidentical HSCT (Wu et al., 2013). All of these results suggest that the infusion of third-party donor-derived UC-MSCs may play a considerable role in the lessening of severe GVHD. A randomized double-blind clinical trial evaluating the use of third-party donor-derived UC-MSC infusion for the prevention

and lessening or treatment of GVHD will be required to establish the efficacy of this treatment regimen. In comparison with other reports (Wang et al., 2009; Fang et al., 2008, 2009; D.P. Lu et al., 2006; L.L. Lu et al., 2006) in which large amounts (over 1 × 106/kg) of MSCs were usually infused intravenously, we administered 5 × 105 cells/kg of UCMSCs to all of the patients, and the clinical outcome was better, with milder GVHD and stable engraftment. Our results indicate that this dose of UC-MSCs retained an effective role. Furthermore, no adverse UC-MSC infusion-related events occurred with the administration of donor UC-MSCs into all patients. In conclusion, our data demonstrate that the modified haplo-HSCT combined with third-party donor-derived UC-MSCs for patients with SAA was not only safe but also effective for the improvement of donor engraftment and the lessening of severe GVHD. Therefore, this treatment regimen may provide a feasible option for the salvage treatment of acquired SAA.

Patients and methods Patients and study design Twenty-one patients with SAA aged 4 to 31 (median 18 years), including 11 males and 10 females were enrolled in this study in

Cotransplantation for severe aplastic anemia Table 2

135

The outcome of transplantations in 21 patients.

Case

ANC N 0.5 × 109/L (D)

PLT N 20 × 109/L (D)

aGVHD grade

cGVHD

Chimerism M1

Outcome (M)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

16 12 16 10 11 14 11 11 13 12 12 21 13 13 10 10 8 9 10 12 10

17 14 18 11 11 16 11 13 13 15 12 23 15 15 14 14 14 10 14 14 12

Ib III a,b,c II a,b No IV a,b,c Ia No III b,c II c No No No III b,c No II c No III c II b,c No I a No

Lim a No Lim a,b No Ext a,c Lim a Ext a,c,e Ext a,c,d No No Lim a,b No No No No Lim b No No No No No

100% 96.6% 100% 100% 100% 98.5% 97.8% 100% 100% 95.7% 99.5% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100%

Alive 78 Dead 5, infection Alive 41 Alive 39 Dead 6, GVHD Dead 13, infection Alive 32 Alive 18 Alive 16 Dead 3, infection Alive 20 Alive 13 Alive 11 Alive 10 Alive 7 Alive 6 Alive 4 Alive 4 Alive 3 Alive 7 Alive 3

ANC, absolute neutrophil count; PLT, platelets; aGVHD, acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease; Ext, extensive; Lim, limited; D, day; M, months. M1:the first month after transplantation. a Organ was affected by GVHD: liver. b Organ was affected by GVHD: skin. c Organ was affected by GVHD: intestinal. d Organ was affected by GVHD: lung. e Organ was affected by GVHD: eye.

our center from January 2007 to June 2013. Detailed information about the patients and preparation of donors were listed Supplementary materials 1 and in Table 4 (Camitta et al., 1979). The clinical protocol and consent forms were approved by the institutional review board for human investigation. Patients or their legal guardians provided written informed consent for their inclusion in the study. HLA compatibility was determined by low-resolution DNA techniques for HLA-A and B loci and high-resolution DNA techniques for HLA-DRB1 (Mickelson et al., 1993; Petersdorf et al., 1991).

PFS after Transplantation

Survival Distribution Function

1.0

0.8

0.6

0.4

UC-MSC preparation 0.2

0.0 .00

20.00

40.00

60.00

80.00

months STRATA:

Surival

UC-MSCs were purchased from the National Engineering Research Center of Cell Products, State Key Laboratory of Experimental Hematology. The immunophenotype of UC-MSCs was listed in Supplementary materials 2 (D.P. Lu et al., 2006; L.L. Lu et al., 2006).

Censored

Conditioning regimen Figure 1 Disease/progression-free survival (PFS) after transplantation. The probability of 2-year PFS for all patients was 74.1%.

The modified conditioning regimen was based on our previous protocol for HLA-identical sibling HSCT. Conditioning

136

Y. Wu et al.

Allogeneic HSC infusion

Table 3 Summary of adverse and severe adverse events for all patients versus UC-MSC dose. Variable

Total (N = 9)

≥ 1 adverse event ≥ 1 severe adverse event Fatal severe adverse event Highest NCI grade or severity Grade 1 Grade 2 Grade 3 Grade 4 Relationship ⁎

21 16 5

At the start of the study, BM and peripheral blood stem cells (PBSCs) (the percentages of BM and PBSCs were same) were both elected as the source of cellular rescue. Supplementary materials 3 presented the collection method of donor allogeneic HSCs. BM and thawed PBSCs were infused intravenously through a central venous catheter on day 0 and day 1 respectively.

2 1 2 16

UC-MSC infusion

Not related Related

17 4

At each level of summation (except for the row for ≥ 1 adverse event), the patients who reported more than 1 event were counted only once. Data are the number of patients. ⁎ Not related indicates an unrelated or unlikely relationship; related indicates a possible, probable, or definite relationship.

procedures included 1 of 2 regimens: (1) fludarabine (Flu) 30 mg/m2/day (days − 5 to − 2), cyclophosphamide (Cy) 600 mg/m2/day (days − 5 to − 2) and ATG 5 mg/kg/day (days − 4 to − 1) (Fig. 2A); or for SAA & PNH only (2) busulfan (Bu) 0.6 mg/Kg/6 h (days − 8 to − 5), Cy 1.8 g/m2/day (days − 4, − 3), and ATG 5 mg/kg/day (days − 4 to − 1) (Fig. 2B) (Wang et al., 2009; Fang et al., 2008, 2009).

The planned UC-MSC dosing scheme was 5.0 × 105/kg in all patients. Before a planned UC-MSC infusion, the cells were shipped in liquid nitrogen containers to our transplantation center. BM infusions were performed 4 h after the completion of UC-MSC infusion.

Prophylaxis and treatment of GVHD GVHD prophylaxis consisted of intravenous CsA 3 mg/kg/day in divided doses beginning the day before transplantation (day − 5) and was continued thereafter. The oral MMF dose was 20 mg/kg/day from day − 1 and was tapered off after 100 days if no aGVHD was observed. Rabbit ATG (Fresenius AG, Oberursel, Germany) was administered intravenously at a dose of 5 mg/kg/day only on days − 4 to − 1 before HSCT, and CD25Ab (Basiliximab, Novartis Pharma Stein AG, Switzerland) was administered intravenously at a dose of 0.5 mg/kg/day only on day 4 after HSCT. Patients were advanced to oral cyclosporine as tolerated. In the absence of GVHD, the oral

A Flu+CTX

-5 -4 -3 -2

BMSC PBSC

-1

ATG

0 +1

+4

MSC

+30

+100

CD25Ab MMF+CSA

B BU

-8

-7

-6 -5

CTX

-4

BMSC PBSC

-3 -2 -1

0 +1

ATG

MSC

+4

+30

+100

CD25Ab MMF+CSA

Figure 2 Sketch of conditioning procedures. Conditioning included 1 of 2 regimens: (A) fludarabine (Flu) 30 mg/m2/day (days − 5 to − 2), cyclophosphamide (Cy) 600 mg/m2/day (days − 5 to − 2) and ATG 5 mg/kg/day (days − 4 to − 1); or for SAA & PNH only (B) busulfan (Bu) 0.6 mg/Kg/6 h (days − 8 to − 5), Cy 1.8 g/m2/day (days − 4, − 3), and ATG 5 mg/kg/day (days − 4 to − 1). ATG, rabbit anti-human T-lymphocyte immunoglobulin; CD25Ab, anti-CD25 antibody; MMF, mycophenolate mofetil; CsA, cyclosprin A.

Cotransplantation for severe aplastic anemia Table 4

137

Supportive care

Patient demographic summary.

Characteristic Age (Y) Median Range Age at transplant (Y) ≤ 10 11–20 21–30 N 30 Disease and status at transplantation SAA VSAA SAA & PNH Time from diagnosis to transplantation (M) Median Range ≤6 13–36 ≥ 37 Sex Male Female Patient/Donor pairs 3 HLA loci 2 HLA loci ABO pairs Pairs Un-pairs Donor–recipient sex match Match Un-match Donor–recipient relationship Mother–child Father–child Siblings CMV-positive donor CMV-positive patient

Data 18 4–31 2(9.5%) 11(52.4%) 7(33.3%) 1(4.8%) 7(33.3%) 12(57.2%) 2(9.5%) 6 1–128 11(52.4%) 5(23.8%) 5(23.8%) 11 (52.4%) 10(47.6%) 12(57.2%) 9 (42.8%) 12(57.2%) 9 (42.8%) 13(61.9%) 8(38.1%) 10(47.6%) 5(23.8%) 6(28.6%) 5(23.8%) 12(57.2%)

SAA, severe aplastic anemia; VSAA, very severe aplastic anemia; PNH, paroxysmal nocturnal hemoglobinuria; Y, year; M, months.

cyclosporine dose was reduced weekly by approximately 5% beginning on or near 6 months, and therapy was usually discontinued by one year after transplantation. Acute and chronic GVHD were treated according to institutional practices.

Engraftment, toxicity grading, GVHD grading and disease assessment All calculations were assessed from the day of HSC and UC-MSC infusions (designated as day 0). Neutrophil and platelet engraftment and hematopoietic chimerism evaluation have been described in supplementary materials 4. Toxic effects were graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE version 4.0). Acute and chronic GVHD was defined and graded as Supplementary materials 5 (Storb et al., 1986; Atkinson et al., 1989). Relapse was defined as the recurrence of disease. Death in the absence of persistent relapse was categorized as nonrelapse mortality.

All of supportive cares were listed in the Supplementary materials 6.

Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.scr.2013.10.001.

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Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells for severe aplastic anemia: successful engraftment and mild GVHD.

Haploidentical hematopoietic stem-cell transplantation (haplo-HSCT) is associated with an increased risk of graft failure and severe graft-versus-host...
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