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


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.


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


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.


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.


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

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).


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).


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


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).


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.


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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).

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