Encouraging results from a small sample of patients with myelodysplastic syndrome (MDS) undergoing haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT) must be extended. Furthermore, an algorithm derived from a comparison of the outcomes of HID and identical-sibling donor (ISD) HSCT must be established. Therefore, the outcomes of 454 MDS patients who underwent HSCT from HIDs (n=226) or ISDs (n=228) between 2003 and 2013 that were reported to the Chinese Bone Marrow Transplantation Registry were analyzed. Among the 3/6 HID (n=136), 4–5/6 HID (n=90) and ISD patient groups, the 4-year adjusted cumulative incidences of non-relapse mortality were 34, 29 and 16%, respectively (overall P=0.004), and of relapse were 6, 7 and 10%, respectively (overall P=0.36). The 4-year adjusted probabilities of overall survival were 58, 63 and 73%, respectively (overall P=0.07), and of relapse-free-survival were 58, 63 and 71%, respectively (overall P=0.14); pairwise comparison showed that the difference was only statistically significant in the 3/6 HID vs ISD pair. The data suggest that ISDs remain the best donor source for MDS patients while HIDs (perhaps 4–5/6 HID in particular) could be a valid alternative when an ISD is not available; human leukocyte antigen disparity had no effect on survival among the HID patients.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with myelodysplastic syndrome (MDS) is a curative treatment approach.1, 2, 3, 4 Notable improvement in haploidentical HSCT now allows it to be widely performed.5, 6, 7 Recently, our institute reported the results of HSCT from haploidentical donors (HIDs) in 36 patients diagnosed with advanced MDS.8 Other groups are prospectively investigating the efficacy of reduced-intensity conditioning in haplo-HSCT for acute leukemia and MDS.9, 10 However, these transplants are being performed in the absence of any large-scale data regarding outcomes of haplo-transplantation for patients with MDS.
There are also limited data to help determine the choice of donor source and in particular whether HIDs could be a valid alternative to identical-sibling donors (ISDs) in MDS. The decision to recommend HSCT is a complex one and requires comprehensive understanding of the disease biology, the expected outcomes with different treatment modalities and the impacts of different donor sources on post-transplant outcomes. Prior analyses demonstrated similar survival after haploidentical HSCT vs ISDs HSCT for all hematological malignancies11 as well as for acute myeloid leukemia (AML) patients in first complete remission.12
MDS patients inherently differ in many ways from patients with de novo AML and it is crucial to define the features associated with the outcomes of HSCT for MDS patients. Results from haploidentical HSCT have not been compared with those of allo-HSCT using ISDs in MDS to evaluate the value of haploidentical HSCT in this specific disease. It is unlikely that a randomized study will ever address this issue and only extrapolation from registry-based studies will help resolve this issue. With this aim, using the large multicenter observational database of the Chinese Bone Marrow Transplant Registry in this disease-specific study, we examined the outcome after HID and ISD HSCT for patients with MDS. In addition, we aimed to identify the pretransplantation patient-, donor- and transplantation-related risk factors that affect the transplant outcomes.
Patients and methods
The patient population consisted of patients with MDS, including those with transformation to AML (tAML) undergoing allogeneic HSCT in China between 2003 and 2013, who had comprehensive data reported to the Chinese Bone Marrow Transplant Registry. A total of 456 cases fulfilling the inclusion criteria were identified from 14 centers (Supplementary Information). Of these, 228 received HID transplants and 228 received ISD transplants. Because there were only two 6/6 haplo-matched HSCTs, these two cases were excluded. Because only 55 MDS patients with unrelated donors were available in Chinese transplant registry, no related comparison was considered due to lack of statistical power. Thirty-six of the patients transplanted in Peking University have been previously reported.8 All patients gave informed consent according to the procedures required by the Institutional Review Board of each center and in accordance with the Declaration of Helsinki.
Among the 14 centers in the Chinese Bone Marrow Transplant Registry mega-file, we found that the annual median number of allo-transplantations performed by the same transplant centers was 75 and this number was used to discriminate between large and small centers, as proposed by the European Blood and Marrow Transplant group.13 Based on this definition, seven transplant centers performing a median of 56 haplo-HSCTs and more than 75 allo-transplantations were classified as large centers, whereas the other seven transplant centers performing a median of 10 haplo-HSCT and fewer than 75 allo-transplantations were classified as small centers.
Disease stages were categorized according to the French–American–British (FAB) classification14 for patients with less than 20% myeloblasts at any time between diagnosis and HSCT. However, all patients with 20% myeloblasts or more were considered as having tAML, based on the World Health Organization classification.15 Cytogenetic risk was assigned for MDS and tAML patients based on the categories of the International Prognostic Scoring System.16 Refractory anemia with excess blasts, tAML and chronic myelomonocytic leukemia were defined as advanced disease according to a previous report.17 Owing to missing data on evaluation of baseline depth of cytopenias, we were unable to use International Prognostic Scoring System-Revised18 to risk stratify patients.
We considered allogeneic HSCT for patients with advanced MDS. Patients with lower-risk MDS (refractory anemia or refractory anemia with ringed sideroblasts) who had poor prognostic features19 and/or signs of progression or sustained profound cytopenia (defined as a neutrophil count <0.5 × 109/l and/or platelet count <20 × 109/l) were also considered as candidates for allogeneic HSCT.
Donor selection and human leukocyte antigen typing
A human leukocyte antigen (HLA)-matched sibling donor was the first choice for allotransplant. If an HLA-matched sibling donor was unavailable subjects without a suitable closely HLA-matched unrelated donor (>8 of 10 matching HLA-A, B, C, DR and DQ loci and >5 of 6 matching HLA-A, B and DR loci) or whose disease state left insufficient time for an unrelated donor search were eligible for HLA haplotype mismatched transplant. HLA typing has been previously described in detail.12 Each patient received stem cells from a family member who shared one HLA haplotype with the patient but differed to a variable degree for the HLA-A, B and DR antigens of the unshared haplotype. In addition to each donor–recipient pairs, HLA typing was done for parents and offspring for a strict analysis to guarantee true haploid genetic background.
Granulocyte colony-stimulating factor (5 μg/kg per day) was used to mobilize bone marrow (G-BM) and peripheral blood (G-PB). The target mononuclear cell count was ⩾6 × 108/kg recipient patient weight. Fresh and un-manipulated BM (harvested on day 4 after granulocyte colony-stimulating factor) and PB stem cells (PBSCs, harvested on day 5 after granulocyte colony-stimulating factor) were infused into the recipient on the day of collection.
For HID patients, pre-transplant conditioning was with cytarabine (4 g/m2/day, days –10 to –9), busulfan (4 mg/kg/day, orally days –8 to –6 before January, 2008 and 3.2 mg/kg/day intravenously (IV) days –8 to –6 thereafter), cyclophosphamide (1.8 g/m2/day days –5 to –4), semustine (250 mg/mE+2 day –3) and rabbit antithymocyte globulin (Thymoglobulin; Imtix Sangstat, Lyon, France; 2.5 mg/kg/day days –5 to –2). ISD patients received a regimen identical to that of HID patients except that ISD patients received hydroxycarbamide (80 mg/kg total dose) and a lower dose of cytarabine (2 g/m2 once), and no antithymocyte globulin. All patients received cyclosporine, mycophenolate mofetil and short course methotrexate for graft-versus-host disease (GVHD) prophylaxis.
Prophylactic donor lymphocyte infusion
In Peking University after 2009, patients who had tAML and had not achieved complete remission (CR) at the time of transplant received prophylactic modified donor lymphocyte infusion (DLI) without active GVHD for the prevention of relapse. The modified DLI regimen was previously described.20 Granulocyte colony-stimulating factor-primed PBSCs were used for DLI.
Study end points and definitions
End points were overall survival (OS) and relapse-free survival (RFS). We also investigated non-relapse-mortality (NRM), incidence of relapse and incidence of acute and chronic GVHD (aGVHD and cGVHD). Survivors were censored at last contact. RFS was defined as time to treatment failure (death or relapse). NRM was defined as death from any cause in the first 28 days post HSCT or death without evidence of disease recurrence beyond day 28. Relapse was defined as disease morphological recurrence as reported by the centers. Assessments of engraftment, chimerism and GVHD were previously described in detail.11
The OS and RFS were reported for 4 years. NRM, relapse, engraftment and GVHD were estimated as cumulative incidences, taking into account competing risks. Competing events were defined as follows: for GVHD, engraftment and relapse, death from any cause; for NRM, relapse. Probabilities of OS and RFS were calculated using the Kaplan–Meier estimator with the log-rank test. Multivariate analyses were conducted to identify and adjust for independent predictors of NRM, relapse, RFS and OS. To examine HLA-loci mismatch effect, which is the variable of primary interest, a three-group comparison was considered: 3/6 HID vs 4–5/6 HID vs ISD HSCT, and forced into the Cox proportional hazards model. Backward elimination with a criterion of P<0.10 for retention was used to select a final model. The following variables were analyzed for their prognostic value regarding each of the transplant outcomes: patient age, disease characteristics (International Prognostic Scoring System score and disease stage at peak) and transplant-related factors (interval between diagnosis and HSCT, donor–recipient sex match, stem cell source, transplant year and large or small centers). Survival probabilities and cumulative incidences were adjusted for the variables listed above and calculated as proposed by Zhang and Zhang.21 The assumption of proportional hazards for each factor in the Cox model was tested. The test indicated that the proportionality assumptions hold. P-value reported from the three-donor group comparison has a two degrees of freedom (d.f.) for the overall test result in fitting a Cox model. Adjusted probabilities were calculated using the SAS software, version 9.4 (SAS Institute, Cary, NC, USA). The SPSS software package (SPSS Inc., Chicago, IL, USA) and R statistical software (Bell Labs, FreeholdBorough, NJ, USA) were used for other data analyses. The end point of the last follow-up for all of survivors was 30 June 2015. Median follow-up of survivors was 48 months (range, 18–150 months).
As shown in Table 1, a statistically significant difference between donor types was observed for age, source of stem cells, donor–patient sex pair and transplant year.
By day 28 post HSCT, the adjusted cumulative incidence of neutrophil recovery was comparable among the 3/6 HID, 4–5/6 HID and ISD groups at 95% (95% confidence interval (CI), 93–98%), 96% (CI, 93–99%) and 95% (CI, 93–97%), respectively; overall P=0.52 (Table 2 and Figure 1a). In contrast, by day 100 the adjusted cumulative incidence of platelet recovery differed significantly (77% (CI, 70–84%), 85% (CI, 79–92%) and 91% (CI, 87–95%), respectively; overall P=0.003), and a pairwise comparison revealed that the difference was more prominent in 3/6 HID vs ISD pair (Table 2 and Figure 1b). Chimerism analysis showed 100% donor chimerism at one month post HSCT in patients with neutrophil recovery.
By day 100, the adjusted cumulative incidence of grades 2 to 4 aGVHD was significantly higher in recipients of 3/6 or 4–5/6 HID transplant than in recipients of ISD transplant (30% (CI, 22–39%), 29% (CI, 19–40%) and 14% (CI, 10–19%), respectively; overall P=0.001) (Table 2 and Figure 1c); however, the adjusted cumulative incidence of grades 3 to 4 aGVHD did not differ (5% (CI, 2–9%), 11% (CI, 4–18%) and 7% (CI, 4–11%), respectively; overall P=0.51). In contrast, the 4-year adjusted cumulative incidence of cGVHD was significantly lower in 3/6 HID group (35% (CI, 28–43%), 48% (CI, 37–60%) and 51% (CI, 46–57%); overall P=0.04) (Table 2 and Figure 1d). Among HID patients, maternal donor (n=29) tended to be associated with higher aGVHD compared with other family relationships (42% (CI, 22–62%) vs 26% (CI, 20–32%); P=0.06).
The 4-year adjusted cumulative incidence of NRM was significantly higher in 3/6 or 4–5/6 HID transplantation than in the ISD HSCT recipients (34% (CI, 26–43%), 29% (CI, 20–39%) and 16% (CI, 12–21%), respectively; overall P=0.004), and a pairwise comparison showed that the difference was more prominent in 3/6 HID vs ISD pair (Tables 2 and 3, and Figure 1e). As within HID cohort, disease duration longer than 12-months (n=54) (39% (CI, 26–52%) vs 27% (CI, 19–35%); P=0.04) rather than 6-months (n=94) (31% (CI, 22–40%) vs 28% (CI, 20–36%); P=0.39) was correlated with significantly lower NRM.
The 4-year adjusted cumulative incidence of relapse (CIR) was similar among 3/6 HID, 4–5/6 HID transplantation and the ISD HSCT recipients (6% (CI, 2–11%), 7% (CI, 3–12%) and 10% (CI, 7–13%), respectively; P=0.36) (Tables 2 and 3 and Figure 1f). Of note, among tAML patients who were older than 40 years and who had not achieved CR (n=41) at the time of transplant, there was a marked trend of lower relapse rates in HID patients (n=16) compared with ISD patients (n=25) (21% (CI, 0–42%) vs 44% (CI, 24–64%); P=0.06); the rates were 23, 20 and 44% in 3/6 HID, 4–5/6 HID and ISD patients (P=0.19), respectively, in univariate analysis.
Among patients with advanced MDS, relapse rate was lower in patients who had not received therapy (n=221) compared with those who did (n=161) (7% (CI, 4–10%) vs 21% (CI, 15–27%); P<0.001). In addition, among patients with advanced MDS, compared with patients who had not received induction chemotherapy, the hazard ratio (HR) for relapse was comparable to patients who achieved CR after chemotherapy (n=61) (HR 1.72; 95% CI 0.68–4.27; P=0.23) but significantly higher in patients who had been treated but did not respond (n=100) (HR 4.82; 95% CI 2.51–9.15; P<0.001).
Among the 41 haploidentical patients who had tAML and had not achieved CR at the time of transplant, 14 received prophylactic modified DLI, the 4-year CIR was 7% (CI, 0–21%) and 28% (CI, 10–46%) for patients with or without prophylactic DLI, respectively. Moreover, 17 patients received interventional modified DLI for positive minimal residual disease detection and 4 out of the 17 patients eventually relapsed during the follow-up.
The 4-year adjusted probabilities of OS and RFS were lower in 3/6 or 4–5/6 HID transplantation than in the ISD HSCT recipients (58% (CI, 50–67%), 63% (CI, 54–73%) and 73% (CI, 67–79%), respectively; overall P=0.07; and 58% (CI, 50–67%), 63% (CI, 54–73%) and 71% (CI, 65–77%), respectively; overall P=0.14), and pairwise comparison showed that the difference was only statistically significant in 3/6 HID vs ISD pair (Tables 2 and 3, and Figures 1g and h). Power analysis for OS showed that it achieves 88% power at a 0.05 significance level for 3/6 HID vs ISD comparison and the power was 59% at a 0.05 significance level for 4–5/6 HID vs ISD comparison. For patients with advanced MDS (n=382), less prominent difference in survival was observed between the three donor groups (overall P=0.22). Pairwise comparison showed that in comparison with ISD patients (n=190), HR for mortality rate was comparable to that of 4–5/6 HID patients (n=74) (HR 1.13; 95% CI 0.72–1.77; P=0.58) and tended to be higher in 3/6 HID patients (n=118) (HR 1.42; 95% CI 0.95–2.11; P=0.09). Power analysis for OS among advanced patients showed that it achieves 86% power at a 0.05 significance level for 3/6 HID vs ISD comparison, while the power was 36% at a 0.05 significance level for 4–5/6 HID vs ISD comparison. Table 4 summarizes the causes of death by donor type as reported by the transplant centers.
For patients older than 45-years (n=129), children donors (n=33) resulted in a survival similar to ISDs (n=76) and a significantly improved 4-year OS compared with haploidentical sibling donors (n=20): 56% (CI, 38–74%), vs 57% (CI, 45–69%), vs 22% (CI, 2–42%) (P=0.01). OS and RFS between large and small centers were not significantly different when adjusted for pre- and post-transplant variables (HR 0.74; 95% CI 0.50–1.09; P=0.13; HR 0.76; 95% CI 0.52–1.12; P=0.17, respectively).
Among patients with advanced MDS, RFS was higher in patients who had not received therapy compared with those who did (67% (CI, 61–73%) vs 57% (CI, 49–65%); P=0.03). In addition, among patients with advanced MDS, compared with patients who had not received induction chemotherapy, HR for RFS was comparable to patients who achieved CR after chemotherapy (HR 0.93; 95% CI 0.56–1.54; P=0.77) but significantly lower in patients who had been treated but had not responded (HR 1.79; 95% CI 1.25–2.57; P=0.001).
Efforts are underway to utilize haploidentical transplants more frequently because preliminary observations suggest an acceptable rejection frequency and a surprisingly low incidence of GVHD.1, 8, 10 However, this approach is currently considered investigational, and further data are required before firm recommendations can be made. Therefore, in an attempt to validate the use of HIDs for patients with MDS/tAML, we undertook the present registry-based comparative study, which by far the largest HID transplantation reported for this specific disease.
The 28-day absolute neutrophil cell recovery in HID cohort was not significantly different from that in the ISD group; additionally, the rate is similar to or higher than that in other reports for MDS, ranging from 85 to 93%.1, 2, 322, 23 Furthermore, although HID patients had more frequent aGVHD, neither severe GVHD nor GVHD-related death was increased in HID cohort. Within HID cohort, risk factor analysis confirmed our previous observation that maternal donor being the worst regarding GVHD occurrence, while the extent of HLA disparity had no effect.7, 24 Conversely, it is counterintuitive that ISD patients had more cGVHD. The reason for this is not clear, although there are some possible explanations. First, in our previous studies, cGVHD either was comparable between HID and ISD patients with all hematologic malignancies11 or occurred more often in HID patients with AML compared with the frequency in ISD patients.12 It is conceivable that the contradictory finding in the current study is disease-specific, which is supported by other reports that mismatched HSCT resulted in lower cGVHD compared with matched HSCT among MDS patients.22, 25 Second, more PBSCs as a graft source in the ISD group compared with that in the HID group may have contributed to more cGVHD occurrence among ISD patients.26
In our report, the NRM rate in HID patients was significantly higher (more prominent in 3/6 HID group) than that in the ISD group, but the NRM rate was similar to or lower than that reported in other studies of MDS, ranging from 28 to 66%.1, 2, 3, 4, 22, 23 Nonetheless, our patients were relatively young compared with recent reports (median age 47–54)10, 22, 23 and this may have contributed to reduction in NRM, although median age of our cohorts was comparable to that in earlier studies of HID (median age 32),1 ISD (median age 38)3 or unrelated donor (median age 38)2 HSCT for patients with MDS. Several causes may account for the significantly different NRM rates between the current cohorts. First, in our previous report, NRM was as low as 10% and comparable between HID and ISD patients with AML transplanted in first complete remission.12 The differences inherent in the disease biology of MDS and de novo AML may lead to the much higher NRM in MDS compared with that in AML as well as the more overt difference between HID and ISD patients with MDS. This result is in agreement with observations from a Korean group9 and European groups.4 Second, the disease duration had a distinct impact on NRM in the HID cohort but not in the ISD cohort (P=0.76, data not shown). Some researchers have found no impact of disease duration on NRM among ISD recipients,3, 4 although opposite result has been reported.23, 27 In addition, the influence of disease duration within the HID group was more apparent with a 12-month cutoff time than with a 6-month cutoff (see Results). Furthermore, the negative effect of later transplantation may be partly attributed to frequent blood transfusions, longer duration of pancytopenias and increased risk of progression during the waiting period for HSCT.28 Given that the longer disease duration, the higher the NRM rate among HID patients, HID patients with MDS, in particular, should undergo HSCT earlier.
The relapse rate in the current study was comparable between the groups. However, the rate was much lower than that reported in other studies of MDS, ranging from 14 to 41%.1, 2, 3, 4, 10, 22, 23 Again, one must keep in mind that our relatively younger group of patients was able to receive myeloablative conditioning, in contrast to recent reports with all or nearly half of the patients undergoing reduced-intensity conditioning,10, 22 although myeloablative conditioning was employed in earlier studies.1, 2, 3 Several reasons may contribute to the low CIR for our HID patients. First, HID transplantation might have a stronger graft-versus-tumor effect than ISD transplantation. The current data showed that there was a trend for lower CIR in the HID patients compared with the ISD patients with refractory disease. This result is in consistent with our previous records among leukemia patients.29 Second, the administration of a modified DLI may play a role. Both the prophylactic DLI for the refractory patients (see Results) and the interventional DLI guided by a positive MRD may be of value;20, 30 however, the fairly small sample size of these subgroups of patients prohibited a meaningful statistical comparison. Third, our results may also be affected by the combined use of G-BM and PB as grafts for the HID patients. Our recent data suggest that transplantation with G-BM and PB results in superior clinical outcomes (a higher RFS and a tendency for lower CIR) compared with G-PB for patients with acute leukemia.31 Notably, the finding that pre-transplant chemotherapy did not exert a beneficial effect on relapse among patients with advanced MDS was unexpected but in agreement with our preliminary8 results and those of other investigators,23, 32 although this phenomenon is controversial.33, 34, 35 It is also of note that female-to-male transplantation exerts a better graft-versus-tumor effect as supported by the recent data of Nakasone et al.36
A higher NRM resulted in a tendency for poorer survival among the HID patients (especially 3/6 HID) compared with the ISD patients, while HLA disparity had no effect within the HID cohort. Owing to the lower relapse rate and NRM compared with most other reports, the RFS was higher than that from other reports (some with an older study population as mentioned above), ranging from 25 to 42%.1, 2, 3, 4, 10, 22, 23 Furthermore, our cohorts achieved similar survival rates for patients with advanced MDS. However, the power analysis results showed that 80% power was reached in the comparison between the 3/6 HID vs ISD groups, but not in the comparison between the 4–5/6 HID vs ISD groups. Caution should be taken when interpreting the clinical importance of the current data. Therefore, a larger population in a future prospective study is required to confirm the conclusions. In the current study, the most significant factor affecting survival was patient age. This finding coincides with the outcomes reported by other researchers.3, 4, 23 Much of the negative impact of age on prognosis appears to be due to the frequency of co-morbid conditions with older age.37 Additionally, unrelated donor patients have been found to have higher co-morbidity scores than ISD patients.38 Unfortunately we have insufficient data on co-morbidity to explore this aspect further. In contrast, in our recent report, similar outcomes were achieved in leukemia patients aged 50years and older compared with younger adults undergoing haploidentical transplants.39 MDS patients are generally older and may have a higher burden of co-morbidities, especially a higher prevalence of cardiac complications (indicated in our own previous study and others’ studies40, 41), which potentially could be responsible for the overt impact of older age on poorer outcomes compared with that observed with leukemia patients. Future prospective studies are required to further assess the co-morbidity effect. Taken together, new strategies, such as the modification of conditioning regimens, must be explored to further assure the safety of HID HSCT, especially for elderly patients. Considering the causes of death, infection (especially invasive fungal infection) and organ failure was more frequent among the patients with HID HSCT compared with patients undergoing ISD HSCT. This was in agreement with our own42 and others’ previous studies.22
Another important point we must keep in mind is that variability exists in the transplant performance among Chinese centers. In addition, each center may have its individual unmeasured characteristics that are associated with the outcomes. In our study, despite the unbalanced distribution of HSCT activity, no clear center effect (regarding center size) was documented. We also think that in future prospective studies, it is important that a center effect be further considered and used to adjust for prognostic factors, and steps can thus be taken to address the practice variations among centers.
Our analysis has limitations. Owing to missing data in some of the study’s components, we were unable to compute International Prognostic Scoring System-Revised scores to risk stratify patients. Another limitation is that insufficient data on ferritin, lactate-dehydrogenase and disease response to different lines of treatments limited our ability to incorporate these important variables into the analysis. Importantly, the comparison between the HID and ISD cohorts is retrospective; therefore, certain imbalanced features exist, although we made adjustments in the multivariate analysis.
In conclusion, this registry-based study suggests that in patients with MDS, ISDs remain the best donor source, while HIDs (perhaps 4–5/6 HIDs in particular) could be a valid alternative when an ISD is not available. Efforts are necessary to further decrease NRM, especially with respect to infection and organ failure.
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This work was partly supported by Collaborative Innovation Center of Hematology China, The Key Program of National Natural Science Foundation of China (Grant No. 81230013), National Natural Science Foundation of China (Grant No. 81400143) and Beijing Municipal Science & Technology Commission (No. Z121107002612035, Z141100000214011 and Z151100001615020).
X-JH designed the research; YW and X-JH analyzed the data and wrote the manuscript; and all authors provided patient data and gave final approval for the manuscript.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Leukemia website
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Wang, Y., Wang, HX., Lai, YR. et al. Haploidentical transplant for myelodysplastic syndrome: registry-based comparison with identical sibling transplant. Leukemia 30, 2055–2063 (2016). https://doi.org/10.1038/leu.2016.110
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