Myeloablative conditioning regimens with combined of haploidentical and cord blood transplantation for myelodysplastic syndrome patients

Abstract

The purpose of this study was to evaluate the strategy of haploidentical (HID) stem cell combined with a small doses of umbilical cord blood (UCB) from a third-party donor transplantation (haplo-cord transplant) for treatment of myelodysplastic syndromes (MDS), by comparing with identical-sibling donor (ISD) transplantation. Eighty-five patients were included between January 2012 and December 2015, with a median 40 years old. Forty-eight patients received haplo-cord transplant and 37 patients received ISD transplant. Haplograft engraftment succeeded in all haplo-cord patients. For haplo-cord and ISD transplantation, adjusted cumulative incidences of grades 2–4 acute GvHD at 100 days were 27 and 11% (P=0.059); adjusted cumulative incidences of chronic GvHD at 2 years were 22 and 34% (P=0.215). The 2-year adjusted probabilities of overall survival were 64 and 70% (P=0.518), and of relapse-free survival were 56 and 66% (P=0.306). The 2-year adjusted cumulative incidences of relapse were 12 and 14% (P=0.743), and of non-relapse mortality were 33 and 23% (P=0.291). In conclusion, haplo-cord-HSCT achieves outcomes similar to those of ISD-HSCT for MDS and the haplo-cord-HSCT may potentially improve the outcome of HID- and UCB-HSCT alone. Thus, the haplo-cord transplantation may be a better valid alternative for MDS when an ISD is not available.

Introduction

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell disorders. Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for MDS and the identical-sibling donors (ISDs) or HLA-matched unrelated donors was the best choice.1, 2 However, it is difficult for Chinese patients to find a suitable ISD or matched unrelated donor due to the population policy. For this, umbilical cord blood transplantation (UCBT) and Haploidentical donors (HIDs) may be a substitute. However, UCBT delayed hematopoietic recovery and immune reconstitution;3, 4 HIDs increased the incidence of acute GvHD (aGvHD), non-relapse mortality (NRM) and infections.5, 6, 7 To overcome these shortcomings, the Spanish group8, 9, 10 combined the infusion of UCB cells with granulocyte colony-stimulating factor mobilized CD34+ selected PBSC from a mismatched relative donor and the results showed fast engraftment, low incidences of GvHD and infections, and promising long-term outcomes. As we previously reported,11 HID combined with the third-party UCB HSCT (haplo-cord-HSCT) also could improve outcomes, reduce the incidences of GvHD and delayed infections, and disease relapse of hematological malignancy. Thus, we first summarized the strategy of haplo-cord-HSCT for MDS patients and compared with ISD-HSCT.

Patients and methods

A total of 102 MDS patients underwent allogeneic HSCT in the First Affiliated Hospital of Soochow University between January 2012 and December 2015. Ninety-four of 102 patients (92.2%) received myeloablative conditioning regimens, whereas the other 7.8% (8/102) patients underwent reduced intensity conditioning regimens. A total of 9.6% (9/94) after matched unrelated donor-HSCT were excluded for lacking of statistical power. Therefore, 85 patients with a median age of 40 (7 to 63) years were included in this study. Thirty-seven patients (44%) received ISD-HSCT and other 48 (56%) received haplo-cord-HSCT. All donors and recipients both had a CMV and EBV seropositive status pre-transplantation. In addition, all recipients were classified according to the 2008 World Health Organization MDS criteria.12 Different risk groups were performed by the International Prognostic Scoring System,13 not using revised International Prognostic Scoring System for missing data, such as neutrophils. Patients were considered to accept allogeneic HSCT when conformed to previous description.6, 14 All recipients and donors provided written informed consent for the protocol, which was approved by our hospital’s Ethics Committee.

Donor selection

All donors and recipients were accepted HLA detection with high-resolution techniques following previous description in detail.6 The selection criteria of HID was according to our previous report.11 The criteria for UCB selection included the following: (1) one unit, (2) UCB unit was HLA 4-5/6 matched with patient, and (3) the count was preferably lower than the minimal thresholds, as required for high probability of engraftment.15

Transplant procedure

All patients received modified BUCY11, 16 as myeloablative conditioning regimen. G-bone marrow (BM) and G-peripheral blood (PB) mobilization of donors, grafts infusion and GvHD prophylaxis in haplo-cord-HSCT were performed as previously reported.11 ISD-HSCT received cyclosporine and short-course methotrexate for GvHD prophylaxis. The methods of diagnosis and treatment for aGvHD and chronic GvHD (cGvHD) were previously described in detail.17, 18

Supportive care

All the patients were in sterile rooms until hematopoietic recovery. Other prevention measures, monitoring methods, treatments of infections and so on were performed according to the previous description.10, 11, 19 The chimerism of donor cells was evaluated by regularly monitoring STRs in the BM and/or peripheral blood cells, according to previous description.11 The regularly monitoring of STR, blasts and dysplastic cells in the marrow were analyzed for diseases relapse.

Donor lymphocyte infusion

Donor lymphocyte infusion was given when the patient relapsed. The detailed regimen for donor lymphocyte infusion administration was previously described.20

Endpoints and definitions

Endpoints

The endpoints were as follows: neutrophil recovery at day 28; platelet recovery at day 100; bloodstream infection at day 30; aGvHD at day 100; BK virus reactivation at day 180; CMV and EBV viremia at 1-year; cGvHD, NRM, relapse, relapse-free survival (RFS) and overall survival (OS) at 2 years post HSCT.

Definitions

Myeloid and platelet recovery were defined according to previous report.11 CR was defined as BM blast <5%, whereas other was defined as non-remission. Relapse was defined as BM blast 5% accompanied with STR decline (STR <90%). Assessments of chimerism and the definition of NRM and RFS were previously described in detail.6, 21

Statistical analysis

The χ2- or Fisher’s exact test was used to compare categorical variables, whereas the non-parametric test was used for continuous ones. To examine effect of haplo-cord-HSCT, the comparison between haplo-cord- and ISD-HSCT was forced into all analysis. Other prognostic variables contained as follows: patient sex and age, disease characteristics (disease type, International Prognostic Scoring System score and disease status pre-HSCT) and transplant-related factors (interval between diagnosis and HSCT, Karnofsky score pre-HSCT, stem cell source, donor–recipient blood type and sex match). The Kaplan–Meier method with the log-rank test was used to calculate the probabilities of OS and RFS for 2 years, whereas Gray test22 was implemented for other analyses. Engraftment, bloodstream infection, viremia, aGvHD, cGvHD, NRM and relapse were estimated as cumulative incidence rate (CIR), taking into account competing risks. Competing events were defined as follows: for engraftment, death from any cause without engraftment; bloodstream infection and viremia, death from any cause without any infection above mentioned; for GvHD, engraftment failure and relapse, death from any cause; for NRM, relapse. Candidate variables with P<0.10 in univariate analysis were reserved and incorporated in multivariate analyses. Backward elimination with the Bayesian information criteria23 was performed in multivariate analyses to identify the independent variables adjusted for the CIR and survival probabilities in the final model. The proportionality hazards assumptions for each variable was tested and hold in the Cox model. Adjusted probabilities were calculated as previous reported,24 by using the SAS software version 9.4. R (SAS Institute, Cary, NC, USA) software, version 3.33 (R Foundation for Statistical Computing, Vienna, Australia) was used for other analyses. The P-value was at the routine 5% significance level. The deadline for follow-up was 28 February 2017, with a median follow-up time of 22.8 (0.1–59.7) months.

Results

Patient demographics

The characteristics of 85 patients are shown in Table 1. Both the stem cell source and donor–patient sex match were significantly different between haplo-cord- and ISD-HSCT (P<0.05). The cells counts of the haplo- and CB grafts were shown in Table 2, whereas Supplementary Tables S1–S3 presented univariate analysis. Finally, all of haplo-cord patients achieved continuously complete HID chimerism (>95%). During the process of engraftment, all patients had engraftment with haplograft only, without evidence of UCB or mixed engraftment.

Table 1 Patient and graft characteristics
Table 2 Infused cell dose of haplo-graft and unrelated CB unit

Hematopoietic recovery

The median time of neutrophil recovery in haplo-cord- (45/48) and ISD-HSCT (36/37) was 12 (range 9–19) and 12 (range 10–20) days (P=0.883). The adjusted CIR of neutrophil recovery was similar among them, with 91% (95% confidence interval (CI) 84~98%) and 94% (95% CI 88~99%) (P=0.443, Figure 1a). The median time to platelet recovery at day 100 of haplo-cord- (44/48) and ISD-HSCT (36/37) was 14 (range 11–39) and 13 (range 11–50) days (P=0.130). However, the adjusted CIR of platelet recovery was significantly lowered in haplo-cord-HSCT, with 89% (95% CI 82~97%) versus 97% (95% CI 94~100%) (P=0.008, Figure 1b). Furthermore, non-remission pre-HSCT was both an inferior factor of neutrophil and platelet recovery (P<0.05) (Table 3).

Figure 1
figure1

Adjusted probabilities of neutrophil recovery (a), platelet recovery (b), acute GvHD (c), chronic GvHD (d), CMV reactivation (e), EBV (f), BK virus (BKV) reactivation (g), bloodstream infection (h), OS (i), RFS (j), relapse (k) and NRM (l) by donor source.

Table 3 Multivariate analysis for relapse, non-relapse mortality, OS and RFS

GvHD disease

Although there was no statistical significance (P=0.059, Figure 1c), the adjusted CIR of grades aGvHD2 at day 100 in haplo-cord-HSCT tended to be higher than ISD-HSCT, with 27% (95% CI 15~39%) and 11% (95% CI 1~20%). However, the adjusted CIR for grades aGvHD 3 at day 100 were similar among them, with 12% (95% CI 3~21%) and 8% (95% CI 0.1~16%) (P=0.481, Figure 1i).

By 2 years, adjusted CIR of cGvHD were 22% (95% CI 10~33%) and 34% (95% CI 19~49%) for haplo-cord- and ISD-HSCT (P=0.215, Figure 1d); the adjusted CIR of extensive cGvHD of them were 14% (95% CI 4~21%) and 13% (95% CI 3~18%) (P=0.870). In addition, refractory anemia with excess blasts was an inferior prognostic factor of aGvHD grades 2 post HSCT (P=0.034; Table 3).

Infectious

By 1 year post HSCT, the haplo-cord-HSCT had a notable higher adjusted CIR of CMV and EBV antigenemia than the ISD-HSCT: with 42% (95% CI 41~43%) versus 14% (95% CI 13~14%) for CMV (P=0.005, Figure 1e), and 46% (95% CI 45~47%) versus 0% (95% CI 0~0%) for EBV (P<0.001, Figure 1f). In addition, no CMV disease or EBV-associated posttransplantation lymphoproliferative disorder were observed in this study.

By day 180, there was no statistical significance about the adjusted CIR of BK virus reactivation between these two group, with 31% (95% CI 19~43%) and 35% (95% CI 20~51%) (P=0.673, Figure 1g). The adjusted CIR of bloodstream infection at day 30 was 27% (95% CI 26~28%) in haplo-cord-HSCT and 16% (95% CI 15~17%) in ISD-HSCT (P=0.257, Figure 1h).

Survival

The causes of death are shown in Table 4. The 2-year adjusted probabilities of OS were similar between the haplo-cord- and ISD-HSCT, with 64% (95% CI 51~77%) and 70% (95% CI 57~84%) (P=0.518, Figure 1i). Similarly, adjusted 2-year probabilities of RFS did not differ significantly between haplo-cord- and ISD-HSCT, with 56% (95% CI 42~69%) and 66% (95% CI 51~80%) (P=0.300, Figure 1j). In addition, a Karnofsky score score <90 and non-remission pre-HSCT both had adverse impacts on OS and RFS (Table 3).

Table 4 Causes of death

Relapse

As of 28 February 2017, 10 patients had relapsed after a median of 8.1 months (range 3.3–22.6), reaching a relapse rate (RR) of 12.3±0.3% at 2 years and all of which received donor lymphocyte infusion (Supplementary Table S4). Haplo-cord- and ISD-HSCT had the similar 2-year adjusted CIR of relapse, with 12% (95% CI 3~20%) and 14% (95% CI 3~25%) (P=0.743, Figure 1j). Furthermore, non-remission pre-HSCT showed an adverse impact on RR (P=0.018, Table 3).

Non-relapse mortality

At a median follow-up of 22.8 months, 23 patients died but without disease recurrence and with 28.1±0.5% NRM at 2 years. The 2-year adjusted CIR of NRM after haplo-cord-HSCT was similar with ISD-HSCT, with 33% (95% CI 19–47%) and 23% (95% CI 10–35%) (P=0.291, Figure 1k). Meanwhile, patients older than 40 years showed a higher NRM (P=0.033, Table 3).

Discussion

Approximately 70% of White and 20% Black patients had an available matched unrelated donor and only 25–30% patients could find ISDs in China.11, 25, 26 HID and UCB were currently considered as alternative donors owing to easily acquiring, low incidence of disease recurrence and similar outcome, and so on. However, the delayed and erratic recovery of immune reconstitution was responsible for the high rate of NRM.4, 6, 11, 27, 28 To evaluate haplo-cord-HSCT for MDS, we showed the strategy of co-infusion of CB as third-party support for HID-HSCT.

During the process of engraftment, haplo-cord patients had engraftment with haplograft only, without evidence of UCB or mixed engraftment, which was different from other studies8, 9, 10 that CB grafts achieved durable engraftment. The lower count and HLA typings of the UCB unit may contribution to the engraftment of haplograft alone.15 Another probable explanation was an immunological graft-versus-graft effect and the absence of T-cell depletion in haplo-cord-HSCT may attribute the preferential engraftment of the haplograft.

We showed the similar median time and the adjusted CIR of neutrophil recovery at day 28 between haplo-cord- and ISD-HSCT, and the neutrophil recovery rate of haplo-cord-HSCT was also similar with ISD-HSCT but higher than other UCBT reports.29, 30, 31 The adjusted CIR of platelet recovery at 100 days after haplo-cord-HSCT was significantly lower than ISD-HSCT. However, this rate of platelet engraftment was higher than UCBT alone.32 In addition, the median time of platelet recovery in our haplo-cord-HSCT was shorter than previous HID-HSCT or UCBT studies.3, 33, 34 Consistent with other studies,10, 11 haplo-cord-HSCT did not delay hematopoietic recovery.

Although haplo-cord-HSCT tended to develop more frequently aGvHD, the rate of aGvHD was substantially lowered compared with those with HID-HSCT and even similar to ISD-HSCT in some cultures of MDS and/or AML. The adjusted CIR of grades 2–4 aGvHD in this cohort was 27%, which was lowered to the previous reports of 36% among 450 AML recipients5 and 60.30±8.7% among 36 MDS recipients.21 In a cohort of 227 MDS/AML patients, Stasi et al.33 reported that the 100-day CIR of grades 2–4 aGvHD in ISD-HSCT was 24%. Other study had shown that the CIR of grades 2–4 aGvHD at 100 days was 27% for ISD-HSCT,35 which was similar to our haplo-cord-HSCT. Our study also showed a similar develop of cGvHD in haplo-cord- and ISD-HSCT, and similar with other studies (ranging from 6% to 20% after HID combined with UCBT).10, 11 Our results suggested that incidence of GvHD was not higher after haplo-cord-HSCT. Graft of UCB may be used as an immuno-modulator to regulate hematopoietic microenvironment and reduce immune rejection, with minor but durable contributions from the haplograft and the host, which may have contributed to the low incidence of GvHD and particularly of aGvHD in our study.36, 37 Meanwhile, G-BM had been demonstrated to cause less cGvHD than mobilized PB grafts in some randomized clinical trials.38, 39 It was possible that the lower rate of cGvHD in the haplo-cord-HSCT may be explained by the greater use of G-BM or/plus G-PB rather than G-PB grafts. In addition, the application of G-CSF to both donors and recipients, antithymocyte and the improvements of utilizing immunosuppressive agents in haplo-cord-HSCT may explain our observations.40, 41

Compared with ISD-HSCT, the incidences of EBV and CMV viremia were higher in haplo-cord-HSCT, which were similar with the previous combined HID and UCBT,10 but lowered than that reported in other HID-HSCT alone, ranging from 65% to 71%.6, 33 For the haplo-cord-HSCT, combined with antithymocyte for GvHD prophylaxis was associated with delayed immune reconstitution and often accompanied by viremia.6, 42 Moreover, UCB contained naive T lymphocytes, it could contribute to the generation of antigen-specific T-lymphocyte immunity early post transplantation,43 which may contribute to lower viremia with haplo-cord-HSCT than HID-HSCT alone. No CMV disease or EBV-related post transplantation lymphoproliferative disorder developed in this study may also due to preemptively treating for viremia.44, 45

Similar to ISD-HSCT, the NRM in our haplo-cord-HSCT was lowered than others after UCBT or HID-HSCT alone.31, 46 The haplograft would achieve reliable early engraftment, which may contribute to the low incidence of post transplant neutropenia-related infections and the low rate of NRM. Another point was that the graft of UCB in haplo-cord-HSCT group could reduce GvHD.11 In addition, our patients were relatively younger (median age 40 years) than those in other studies (median age 47–54 years).29, 47 Those considerations may contribute to the lower NRM in our study. However, the NRM in our haplo-cord-HSCT was higher than other diseases, such as AML transplanted in first CR after HID-HSCT.5 It seemed that delayed HSCT in MDS may result in disease progression or a worsening patient conditioning and then increase NRM.48 Moreover, previous finding49 strongly suggested the important differences in pathophysiology between MDS and AML.

Our study demonstrated that the similar RR in the haplo-cord- and ISD-HSCT. However, a 31% 3-year RR of 176 adult MDS patients after ISD-HSCT was reported29 and higher than 2-year RR of 13% in our haplo-cord-HSCT. Sierra et al.2 showed that the 1-year RR was 17% in 452 MDS patients after ISD-HSCT, which was also higher than our results. Moreover, Chen et al.21 reported a RR of 19.25±9.37% in 36 MDS patients after HID-HSCT by at 2 years and the European Group for Blood and Marrow Transplantation31 reviewed a 2-year RR of 30±4% in 129 MDS patients after UCBT. Both RR of which were higher than ours. As previous study, haplo-cord-HSCT might have a stronger anti-leukemia effect than ISD-HSCT.50 Nevertheless, all of our patients underwent myeloablative, which might have contributed to decrease the RR. Thus, it is possible that the haplo-cord-HSCT affects the RR, but further study will be necessary.

In our haplo-cord-HSCT, the adjusted RFS was higher than other reports, ranging from 28% to 41%.29, 31 In addition, the adjusted OS in haplo-cord-HSCT was also higher than that observed in other previous studies.31, 51, 52 The haplograft would achieve reliable early engraftment, which may contribute to the low incidence of neutropenia-related infections and the high rate of survival. The UCB could result in GvHD prevention and possibly in anti-leukemia effect, thus explaining at least in part the encouraging 2-year OS and RFS in our group. Furthermore, relatively young patients had a better outcomes.6, 33, 53 In addition, previous studies reported that a shorter interval from diagnosis to transplant (<1 year) was associated with better outcomes.54 The median time to transplantation of our patients was only 3 months and most of the patients (80/85) transplanted within 1-year interval, which may contribute to the preferable outcomes. Consistent with the previous literature,53 our study showed a better OS and RFS of patients with CR pre-transplantation.

In conclusion, this study had some limitations due to relatively small number of patients and lack of data of haplo-SCT without UCB or CBT alone in our center. Well-designed prospective research and experimental will be needed to reveal the probable mechanism. With support by small doses of UCB from a third-party donor, HID-HSCT revealed reliable and fast engraftment of platelets and neutrophils, low incidences of GvHD and NRM, promising long-term outcomes. Thus, haplo-cord-HSCT may be a better valid alternative option for MDS patients compares with HID-HSCT or UCBT alone, when an ISD is not available.

References

  1. 1

    Passweg JR, Baldomero H, Bregni M, Cesaro S, Dreger P, Duarte RF et al. Hematopoietic SCT in Europe: data and trends in 2011. Bone Marrow Transplant 2013; 48: 1161–1167.

    CAS  Article  Google Scholar 

  2. 2

    Sierra J, Perez WS, Rozman C, Carreras E, Klein JP, Rizzo JD et al. Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood 2002; 100: 1997–2004.

    CAS  PubMed  Google Scholar 

  3. 3

    Brunstein CG, Gutman JA, Weisdorf DJ, Woolfrey AE, Defor TE, Gooley TA et al. Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Blood 2010; 116: 4693–4699.

    CAS  Article  Google Scholar 

  4. 4

    Ballen KK, Spitzer TR . The great debate: haploidentical or cord blood transplant. Bone Marrow Transplant 2011; 46: 323–329.

    CAS  Article  Google Scholar 

  5. 5

    Wang Y, Liu QF, Xu LP, Liu KY, Zhang XH, Ma X et al. Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood 2015; 125: 3956–3962.

    CAS  Article  Google Scholar 

  6. 6

    Wang Y, Wang HX, Lai YR, Sun ZM, Wu DP, Jiang M et al. Haploidentical transplant for myelodysplastic syndrome: registry-based comparison with identical sibling transplant. Leukemia 2016; 30: 2055–2063.

    CAS  Article  Google Scholar 

  7. 7

    Lu DP, Dong L, Wu T, Huang XJ, Zhang MJ, Han W et al. Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood 2006; 107: 3065–3073.

    CAS  Article  Google Scholar 

  8. 8

    Magro E, Regidor C, Cabrera R, Sanjuan I, Fores R, Garcia-Marco JA et al. Early hematopoietic recovery after single unit unrelated cord blood transplantation in adults supported by co-infusion of mobilized stem cells from a third party donor. Haematologica 2006; 91: 640–648.

    PubMed  Google Scholar 

  9. 9

    Bautista G, Cabrera JR, Regidor C, Fores R, Garcia-Marco JA, Ojeda E et al. Cord blood transplants supported by co-infusion of mobilized hematopoietic stem cells from a third-party donor. Bone Marrow Transplant 2009; 43: 365–373.

    CAS  Article  Google Scholar 

  10. 10

    Liu H, Rich ES, Godley L, Odenike O, Joseph L, Marino S et al. Reduced-intensity conditioning with combined haploidentical and cord blood transplantation results in rapid engraftment, low GVHD, and durable remissions. Blood 2011; 118: 6438–6445.

    CAS  Article  Google Scholar 

  11. 11

    Chen J, Wang RX, Chen F, Sun AN, Qiu HY, Jin ZM et al. Combination of a haploidentical SCT with an unrelated cord blood unit: a single-arm prospective study. Bone Marrow Transplant 2014; 49: 206–211.

    CAS  Article  Google Scholar 

  12. 12

    Brunning RD, Bennett JM, Flandrin G, Matutes E, Head D, Vardiman JW et alMyeodyaplastic syndromes In Jaffe ES, Harris NL, Stein H, Vardiman JW eds.World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haemopoietic and Lymphoid Tissues. LARC Press: Lyon, 2001pp61–73.

    Google Scholar 

  13. 13

    Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088.

    CAS  PubMed  Google Scholar 

  14. 14

    Kroger N, Zabelina T, de Wreede L, Berger J, Alchalby H, van Biezen A et al. Allogeneic stem cell transplantation for older advanced MDS patients: improved survival with young unrelated donor in comparison with HLA-identical siblings. Leukemia 2013; 27: 604–609.

    CAS  Article  Google Scholar 

  15. 15

    Wagner JE, Barker JN, DeFor TE, Baker KS, Blazar BR, Eide C et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 2002; 100: 1611–1618.

    CAS  PubMed  Google Scholar 

  16. 16

    Tian H, Liu L, Chen J, Xu Y, Jin Z, Miao M et al. Haploidentical hematopoietic stem cell transplant in paroxysmal nocturnal hemoglobinuria. Leuk Lymph 2016; 57: 835–841.

    CAS  Article  Google Scholar 

  17. 17

    Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.

    Article  Google Scholar 

  18. 18

    Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.

    Google Scholar 

  19. 19

    Lee YJ, Zheng J, Kolitsopoulos Y, Chung D, Amigues I, Son T et al. Relationship of BK polyoma virus (BKV) in the urine with hemorrhagic cystitis and renal function in recipients of T cell-depleted peripheral blood and cord blood stem cell transplantations. Biol Blood Marrow Transplant 2014; 20: 1204–1210.

    Article  Google Scholar 

  20. 20

    Miyamoto T, Fukuda T, Nakashima M, Henzan T, Kusakabe S, Kobayashi N et al. Donor lymphocyte infusion for relapsed hematological malignancies after unrelated allogeneic bone marrow transplantation facilitated by the Japan Marrow Donor Program. Biol Blood Marrow Transplant 2017; 23: 938–944.

    Article  Google Scholar 

  21. 21

    Chen Y, Liu K, Xu L, Chen H, Liu D, Zhang X et al. HLA-mismatched hematopoietic SCT without in vitro T-cell depletion for myelodysplastic syndrome. Bone Marrow Transplant 2010; 45: 1333–1339.

    CAS  Article  Google Scholar 

  22. 22

    Gray RJ . A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.

    Article  Google Scholar 

  23. 23

    Schwartz G . Estimating the dimension of a model. Ann Stat 1978; 6: 31–38.

    Google Scholar 

  24. 24

    Zhang X, Zhang M. SAS . Macros for estimation of direct adjusted cumulative incidence curves under proportional subdistribution hazards models. Comput Methods Programs Biomed 2011; 101: 87–93.

    Article  Google Scholar 

  25. 25

    Dew A, Collins D, Artz A, Rich E, Stock W, Swanson K et al. Paucity of HLA-identical unrelated donors for African-Americans with hematologic malignancies: the need for new donor options. Biol Blood Marrow Transplant 2008; 14: 938–941.

    Article  Google Scholar 

  26. 26

    Joshua TV, Rizzo JD, Zhang MJ, Hari PN, Kurian S, Pasquini M et al. Access to hematopoietic stem cell transplantation: effect of race and sex. Cancer 2010; 116: 3469–3476.

    Article  Google Scholar 

  27. 27

    Ramirez P, Brunstein CG, Miller B, Defor T, Weisdorf D . Delayed platelet recovery after allogeneic transplantation: a predictor of increased treatment-related mortality and poorer survival. Bone Marrow Transplant 2011; 46: 981–986.

    CAS  Article  Google Scholar 

  28. 28

    Majhail NS, Mothukuri JM, Brunstein CG, Weisdorf DJ . Costs of hematopoietic cell transplantation: comparison of umbilical cord blood and matched related donor transplantation and the impact of posttransplant complications. Biol Blood Marrow Transplant 2009; 15: 564–573.

    Article  Google Scholar 

  29. 29

    Saber W, Cutler CS, Nakamura R, Zhang MJ, Atallah E, Rizzo JD et al. Impact of donor source on hematopoietic cell transplantation outcomes for patients with myelodysplastic syndromes (MDS). Blood 2013; 122: 1974–1982.

    CAS  Article  Google Scholar 

  30. 30

    Barker JN, Scaradavou A, Stevens CE . Combined effect of total nucleated cell dose and HLA match on transplantation outcome in 1061 cord blood recipients with hematologic malignancies. Blood 2010; 115: 1843–1849.

    CAS  Article  Google Scholar 

  31. 31

    Robin M, Ruggeri A, Labopin M, Niederwieser D, Tabrizi R, Sanz G et al. Comparison of unrelated cord blood and peripheral blood stem cell transplantation in adults with myelodysplastic syndrome after reduced-intensity conditioning regimen: a collaborative study from Eurocord (Cord blood Committee of Cellular Therapy & Immunobiology Working Party of EBMT) and Chronic Malignancies Working Party. Biol Blood Marrow Transplant 2015; 21: 489–495.

    Article  Google Scholar 

  32. 32

    Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood 2011; 118: 282–288.

    CAS  Article  Google Scholar 

  33. 33

    Di Stasi A, Milton DR, Poon LM, Hamdi A, Rondon G, Chen J et al. Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transplant 2014; 20: 1975–1981.

    Article  Google Scholar 

  34. 34

    Solh M, Brunstein C, Morgan S, Weisdorf D . Platelet and red blood cell utilization and transfusion independence in umbilical cord blood and allogeneic peripheral blood hematopoietic cell transplants. Biol Blood Marrow Transplant 2011; 17: 710–716.

    Article  Google Scholar 

  35. 35

    Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK et al. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol 2013; 31: 1310–1316.

    CAS  Article  Google Scholar 

  36. 36

    van Besien K, Dew A, Lin S, Joseph L, Godley LA, Larson RA et al. Patterns and kinetics of T-cell chimerism after allo transplant with alemtuzumab-based conditioning: mixed chimerism protects from GVHD, but does not portend disease recurrence. Leuk Lymph 2009; 50: 1809–1817.

    CAS  Article  Google Scholar 

  37. 37

    Gutman JA, Turtle CJ, Manley TJ, Heimfeld S, Bernstein ID, Riddell SR et al. Single-unit dominance after double-unit umbilical cord blood transplantation coincides with a specific CD8+ T-cell response against the nonengrafted unit. Blood 2010; 115: 757–765.

    CAS  Article  Google Scholar 

  38. 38

    Schmitz N, Beksac M, Bacigalupo A, Ruutu T, Nagler A, Gluckman E et al. Filgrastim-mobilized peripheral blood progenitor cells versus bone marrow transplantation for treating leukemia: 3-year results from the EBMT randomized trial. Haematologica 2005; 90: 643–648.

    CAS  PubMed  Google Scholar 

  39. 39

    Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 2012; 367: 1487–1496.

    CAS  Article  Google Scholar 

  40. 40

    Liu D, Huang X, Liu K, Xu L, Chen H, Han W et al. Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for treatment of hematological malignancies in children. Biol Blood Marrow Transplant 2008; 14: 469–477.

    CAS  Article  Google Scholar 

  41. 41

    Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W et al. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 2006; 38: 291–297.

    Article  Google Scholar 

  42. 42

    Tischer J, Engel N, Fritsch S, Prevalsek D, Hubmann M, Schulz C et al. Virus infection in HLA-haploidentical hematopoietic stem cell transplantation: incidence in the context of immune recovery in two different transplantation settings. Ann Hematol 2015; 94: 1677–1688.

    CAS  Article  Google Scholar 

  43. 43

    Cohen G, Carter SL, Weinberg KI, Masinsin B, Guinan E, Kurtzberg J et al. Antigen-specific T-lymphocyte function after cord blood transplantation. Biol Blood Marrow Transplant 2006; 12: 1335–1342.

    Article  Google Scholar 

  44. 44

    Ju HY, Kang HJ, Hong CR, Lee JW, Kim H, Park KD et al. Half-dose ganciclovir preemptive treatment of cytomegalovirus infection after pediatric allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2016; 18: 396–404.

    CAS  Article  Google Scholar 

  45. 45

    Liu Q, Xuan L, Liu H, Huang F, Zhou H, Fan Z et al. Molecular monitoring and stepwise preemptive therapy for Epstein-Barr virus viremia after allogeneic stem cell transplantation. Am J Hematol 2013; 88: 550–555.

    CAS  Article  Google Scholar 

  46. 46

    de Witte T, Pikkemaat F, Hermans J, van Biezen A, Mackinnan S, Cornelissen J et al. Genotypically nonidentical related donors for transplantation of patients with myelodysplastic syndromes: comparison with unrelated donor transplantation and autologous stem cell transplantation. Leukemia 2001; 15: 1878–1884.

    CAS  Article  Google Scholar 

  47. 47

    Chang C, Storer BE, Scott BL, Bryant EM, Shulman HM, Flowers ME et al. Hematopoietic cell transplantation in patients with myelodysplastic syndrome or acute myeloid leukemia arising from myelodysplastic syndrome: similar outcomes in patients with de novo disease and disease following prior therapy or antecedent hematologic disorders. BLOOD 2007; 110: 1379–1387.

    CAS  Article  Google Scholar 

  48. 48

    de Witte T, Brand R, van Biezen A, Mufti G, Ruutu T, Finke J et al. Allogeneic stem cell transplantation for patients with refractory anaemia with matched related and unrelated donors: delay of the transplant is associated with inferior survival. Br J Haematol 2009; 146: 627–636.

    CAS  Article  Google Scholar 

  49. 49

    Walter MJ, Shen D, Shao J, Ding L, White BS, Kandoth C et al. Clonal diversity of recurrently mutated genes in myelodysplastic syndromes. Leukemia 2013; 27: 1275–1282.

    CAS  Article  Google Scholar 

  50. 50

    Wang Y, Liu DH, Xu LP, Liu KY, Chen H, Chen YH et al. Superior graft-versus-leukemia effect associated with transplantation of haploidentical compared with HLA-identical sibling donor grafts for high-risk acute leukemia: an historic comparison. Biol Blood Marrow Transplant 2011; 17: 821–830.

    Article  Google Scholar 

  51. 51

    Devillier R, Bramanti S, Furst S, Sarina B, El-Cheikh J, Crocchiolo R et al. T-replete haploidentical allogeneic transplantation using post-transplantation cyclophosphamide in advanced AML and myelodysplastic syndromes. Bone Marrow Transplant 2016; 51: 194–198.

    CAS  Article  Google Scholar 

  52. 52

    Sharma P, Shinde SS, Damlaj M, Hefazi RM, Hashmi SK, Litzow MR et al. Allogeneic hematopoietic stem cell transplant in adult patients with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes. Leuk Lymph 2017; 58: 872–881.

    CAS  Article  Google Scholar 

  53. 53

    Trottier BJ, Sachs Z, DeFor TE, Shune L, Dolan M, Weisdorf DJ et al. Novel disease burden assessment predicts allogeneic transplantation outcomes in myelodysplastic syndrome. Bone Marrow Transplant 2016; 51: 199–204.

    CAS  Article  Google Scholar 

  54. 54

    Runde V, de Witte T, Arnold R, Gratwohl A, Hermans J, van Biezen A et al. Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 1998; 21: 255–261.

    CAS  Article  Google Scholar 

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Acknowledgements

This study was supported by the great form the National Nature Science Foundation of China (Grant number 81470346), innovation Capability Development Project of Jiangsu Province (BM2015004) and the National Key Research and Development Program (2016YFC0902800).

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Correspondence to S-L Xue or X Ma.

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Ke, P., Bao, XB., Hu, XH. et al. Myeloablative conditioning regimens with combined of haploidentical and cord blood transplantation for myelodysplastic syndrome patients. Bone Marrow Transplant 53, 162–168 (2018). https://doi.org/10.1038/bmt.2017.229

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