This study aimed to compare the therapeutic effects of single umbilical cord blood transplantation (UCBT) and unmanipulated haploidentical hematopoietic SCT (haplo-HSCT) in childhood hematologic malignances. We enrolled 410 consecutive children who received either single UCBT (n=37) or haplo-HSCT from a family donor (n=373) during the same time period. For each UCBT recipient, three recipients matched for year of HSCT, underlying diseases, disease status and the length of follow-up were randomly selected from the haplo-HSCT cohort. Hematopoietic recovery was significantly faster in haplo-HSCT recipients than in UCBT recipients. The incidence of chronic GVHD was significantly higher in haplo-HSCT recipients. The incidence of CMV-related interstitial pneumonia was higher in UCBT recipients. The haplo-HSCT recipients had better 1-year OS (73.0% vs 56.8%, P=0.048), lower 1-year non-relapse mortality (NRM, 18.0% vs 35.1%, P=0.026) and lower 2-year NRM rates (19.9% vs 35.1%, P=0.044). The relapse- and disease-free survival rates did not differ significantly between the groups. Our results showed that compared with UCBT, unmanipulated haplo-HSCT can improve the outcomes of children with hematologic malignances.
Despite recent advances in chemotherapy for the treatment of childhood hematologic malignancies, allogeneic hematopoietic SCT (HSCT) is still an effective therapy and is sometimes the only treatment option. Although a healthy HLA-identical sibling donor is preferred, such a donor is unavailable for many children who present for HSCT owing to a hematologic malignancy. Umbilical cord blood (UCB) has emerged as an alternative source of hematopoietic stem cells. The use of UCB transplantation (UCBT) has some potential advantages. For instance, hematopoietic stem cells from UCB are immunologically naive, which could explain why these cells are associated with a lower rate of immunological complications than adult stem cells. In addition, these cells have a greater expansion and division potentials than adult stem cells. Thus far, several studies have demonstrated the benefits of UCBT in children with hematologic malignancies.1,2
A haploidentical donor is another alternative source of hematopoietic stem cells. The use of haploidentical HSCT (haplo-HSCT) has several advantages, including the relatively short time associated with finding a suitable donor, as well as the greater immunologic reactions against tumor cells associated with haplo-HSCT. In recent years, much progress has been made, and an increasing number of children have achieved long-term survival with haplo-HSCT.3 Liu et al.4 reported the results of 42 children who underwent unmanipulated haplo-HSCT for the treatment of hematologic malignancies. The cumulative incidence of grade III–IV acute GVHD was only 13.8%, and the 3-year probability of leukemia-free survival was 57.3%.
Several studies have compared the outcomes of UCBT and haplo-HSCT. Blood and Marrow Transplantation Clinical Trials Networks (BMT CTN) conducted two parallel phase II trials to evaluate the efficacy of double UCBT and haplo-marrow transplantation. They reported that non-relapse mortality (NRM) was higher after UCBT than after haplo-HSCT, but the relapse rate was higher after haplo-HSCT than after UCBT. The 1-year OS was comparable.5 Kanda et al.6 conducted a retrospective study in which the outcomes of treatment with single UCBT and related transplantation with HLA 1-antigen mismatch in the GVH direction (RD/1AG-MM-GVH) were compared. They found that the survival rate in the UCB group was comparable to that in the RD/1AG-MM-GVH group. However, in these studies most of the patients were adults, and, currently, little information is available regarding the priority of selecting alternative donors for the treatment of childhood hematologic malignances. Therefore, we conducted a matched-pair analysis to compare the therapeutic effects of single UCBT and unmanipulated haplo-HSCT in children with hematologic malignancies.
Materials and methods
Patients aged ⩽18 years with a hematologic malignancy, who lacked a suitable matched related donor, were eligible for alternative donor HSCT. The inclusion criteria were as follows: patients with acute leukemia with clinical and biologic features that indicated a higher risk of relapse with conventional chemotherapy; patients with non-Hodgkin lymphomas with aggressive histology and who had a high risk of subsequent relapse with autologous transplantation (for example, BM involvement, suboptimal response to initial or salvage chemotherapy); patients with CML that was beyond the first chronic phase, resistant/intolerant to treatment with tyrosine kinase inhibitors or unable to meet the costs of long-term therapy with tyrosine kinase inhibitors; and patients with myelodysplastic syndrome who had refractory anemia with excess blasts or who were transfusion dependent (Supplementary Table 1). Children without a suitable UCB donor (donors with at least 4 of 6 matching HLA-A, -B and -DR loci) were eligible to receive transplantation from unrelated donors (URDs, n=36, the results of haplo-HSCT vs URD HSCT and URD HSCT vs UCBT were previously described by Huang et al.7 and Chen et al.,8 respectively, and were not included in this study). Children without a suitable closely HLA-matched URD (donors with more than 8 of 10 matching HLA-A, -B, -C, -DR and -DQ loci and at least 5 of 6 matching HLA-A, -B and -DR loci), or those who had a disease status that did not allow sufficient time for an URD search, were eligible to receive haplo-HSCT. We enrolled 410 consecutive patients who received either single UCBT (n=37) or haplo-HSCT from a family donor (n=373) between January 2000 and October 2012. A matched-pair analysis was designed. For each UCBT recipient, three recipients were randomly selected from the haplo-HSCT cohort and were matched according to the following criteria: year of the HSCT (±2 years), underlying diseases, disease status at transplantation and the length of follow-up (Table 1). The end point of the last follow-up was 31 October 2013. The median follow-up period after HSCT was 3.3 years (range, 0.1–11.8 years) for UCBT and 3.0 years (range, 0.1–11.2 years) for haplo-HSCT recipients. Informed consent was obtained from all the patients’ guardians. The study protocol was approved by the ethics committee of Peking University People's Hospital.
The major preconditioning treatment consisted of cytarabine (4 g/(m2·day), −10 to −9 days), BU (4 mg/(kg·day) administered orally on days −8 to −6 before January 2008 or 3.2 mg/(kg·day) administered intravenously on days −8 to −6 after January 2008), CY (1.8 g/(m2·day), −5 to −4 days) and simustine (250 mg/m2, −3 days), along with rabbit antithymocyte globulin (thymoglobulin, 2.5 mg/kg, −5 to −2 days; Sanofi, Paris, France).7, 8, 9, 10 All of the haplo-HSCT recipients received CsA, mycophenolate mofetil and short-term MTX as prophylaxis for GVHD.9,10 UCBT recipients received methyl prednisolone instead of MTX.8 Patients were monitored weekly for CMV-DNA (real-time polymerase chain reaction) or CMV pp65 antigenemia tests. CMV-positive patients were treated with either ganciclovir or foscarnet. CMV-related interstitial pneumonia was defined according to reported criteria.10 When hematologic or cytogenetic relapse was diagnosed after transplantation, the relapse was treated with immunosuppressant withdrawal, followed by therapeutic DLI.7,11,12 Treatment with imatinib mesylate (Novartis, Switzerland) was initiated for the eligible Ph-positive ALL patients or the CML patients who experienced a cytogenetic or hematologic relapse after HSCT and to patients who showed rising levels (1 log increase) of bcr/abl RNA transcripts by real-time quantitative-polymerase chain reaction.7,13 Detection of the immunophenotype after transplantation was performed as reported previously.14
HLA typing and stem cell harvesting
At our institute, all donor–recipient pairs were typed at the HLA-A, -B and -DR loci. To determine HLA-A and -B status, low-resolution DNA techniques were used. High-resolution techniques were used for HLA-DRB1 typing. The maximum allowable mismatch between the cord blood unit and the recipient was two of six HLA loci. All patients with haplo-HSCT received stem cells from a family member who shared one HLA haplotype with the patient. The HLA-A, -B and -D antigens of the haplotype, which were not shared, differed by varying degrees between donor–recipient pairs. In addition to typing each donor–recipient pair, HLA typing was performed for parents and offspring and strictly analyzed to guarantee true haploid genetic background.8,15
Definition and assessments
High-risk patients were defined as follows: (1) acute leukemia patients in the first or second CR with a cytogenetic marker of ‘poor risk’, including t(4; 11) and t(9; 22); (2) patients in CR after CR3; (3) patients in PR, non-remission or in a state of relapse before HSCT; and (4) patients with CML beyond the first chronic phase. All other patients were stratified into standard-risk categories.7 Neutrophil engraftment was defined as the first day of an ANC of 0.5 × 109/L or more for 3 consecutive days, and platelet engraftment was defined as the first day of a platelet count of 20 × 109/L or more for 7 consecutive days without transfusion. Primary engraftment failure was defined as the absence of donor-derived myeloid cells at day 60 in patients surviving beyond day 28 after transplantation, or as the need for a second allogeneic transplant or reconstitution with autologous cells. The diagnosis of GVHD was in accordance with the common international criteria.16,17 OS was defined as the time from transplantation to death from any cause. Disease-free survival (DFS) was defined as survival in continuous CR. Relapse was defined by morphologic evidence of disease in PB, marrow or extramedullary sites, or by the recurrence and sustained presence of pretransplantation chromosomal abnormalities. Patients who showed minimal residual disease were not classified as having relapsed. NRM was defined as death after HSCT without disease progression or relapse.
Data were censored at the time of death or the last available follow-up. Survival probabilities were estimated using the Kaplan–Meier method. Competing risk analysis was used to calculate the cumulative incidence of engraftments, GVHD, CMV infections, hemorrhage cystitis, relapse and NRM, using the Gray test to test differences between haplo-HSCT and UCBT groups.18 In total population, multivariate hazard ratios for OS and DFS were estimated from Cox proportional-hazards regression, and the multivariate hazard ratios for relapse and NRM were estimated from the Fine and Grey’s proportional-hazards model for subdistribution of a competing risk.19 Factors included in the regression model were age, gender, underlying diseases, disease status at transplantation, donor type, HLA disparity (0–1 vs 2+), donor–recipient sex matched and conditioning regimens. Independent variables with P>0.1 were sequentially excluded from the model, and P<0.05 was considered to be statistically significant. All of the reported P-values were based on two-sided hypothesis tests. Data analyses were primarily conducted with the SPSS software package (SPSS Inc., Chicago, IL, USA), and the R software package (version 2.6.1; http://www.r-project.org) was used for competing risk analysis.
Analysis of chimerism indicated that all patients surviving beyond day 28, except two UCBT recipients who died of primary graft failure, achieved full donor chimerism by day 30 after HSCT. The neutrophil engraftments occurred at a median of 13 days (range, 10–23 days) and 18 days (range, 11–36 days) for the haplo-HSCT and UCBT recipients, respectively (P<0.001). The 100-day cumulative incidence of neutrophil engraftment in the haplo-HSCT group was higher than that in the UCBT group (haplo-HSCT group, 99.6%, 95% confidence interval (95% CI): 98.5–100.0%; UCBT group, 89.2%, 95% CI: 83.7–94.7%, P<0.001). Platelet engraftment occurred at a median of 16 days (range, 7–188 days) and 33 days (range, 7–81 days) for the haplo-HSCT and UCBT recipients, respectively (P<0.001). The 100-day cumulative incidence of platelet engraftment in the haplo-HSCT group was higher than that in the UCBT group (haplo-HSCT group, 93.7%, 95% CI: 89.0–98.4%; UCBT group, 75.7%, 95% CI: 61.3–90.1%, P=0.001).
At day 100 after HSCT, the cumulative incidence of grade II–IV or grade III–IV acute GVHD was comparable between haplo-HSCT and UCBT groups (grade II–IV acute GVHD: haplo-HSCT group, 48.6%, 95% CI: 37.8–59.4%; UCBT group, 42.3%, 95% CI: 24.9–59.7%, P=0.238; grade III–IV acute GVHD: haplo-HSCT group, 16.2%, 95% CI: 9.3–23.1%; UCBT group, 10.8%, 95% CI: 0.6–21.0%, P=0.384).
The 2-year cumulative incidence of chronic GVHD or extensive chronic GVHD in the haplo-HSCT group was significantly higher than that in the UCBT group (chronic GVHD: haplo-HSCT group, 60.5%, 95% CI: 50.4–70.6%; UCBT group, 20.5%, 95% CI: 5.6–35.4%, P=0.003; extensive chronic GVHD: haplo-HSCT group, 21.6%, 95% CI: 16.3–26.9%; UCBT group, 2.7%, 95% CI: 0.0–10.4%, P=0.009).
CMV infection and hemorrhage cystitis
At day 100 after HSCT, the cumulative incidence of CMV antigenemia was 70.3% (95% CI: 61.7–78.9%) in the haplo-HSCT group and 56.8% (95% CI: 40.4–73.2%) in the UCBT group, respectively (P=0.153); however, the cumulative incidence of CMV-related interstitial pneumonia was significantly higher in the UCBT group (haplo-HSCT group, 7.2%, 95% CI 2.4–12.0%; UCBT group, 21.6%, 95% CI 8.1–35.1%, P=0.018).
At day 100 after HSCT, the cumulative incidence of hemorrhage cystitis or grade 3–4 hemorrhage cystitis was comparable between haplo-HSCT and UCBT groups (hemorrhage cystitis: haplo-HSCT group, 36.9%, 95% CI 27.9–45.9%; UCBT group, 27.0%, 95% CI 12.5–41.5%, P=0.307; grade 3–4 hemorrhage cystitis: haplo-HSCT group, 2.7%, 95% CI 0.0–5.7%; UCBT group, 5.4%, 95% CI 0.0–12.8%, P=0.432).
Relapse and NRM
The 1-year or 2-year cumulative incidence of relapse was comparable between haplo-HSCT and UCBT groups (1-year relapse: haplo-HSCT group, 14.4%, 95% CI 7.8–21.0%; UCBT group, 10.8%, 95% CI 0.6–21.0%, P=0.580; 2-year relapse: haplo-HSCT group, 18.0%, 95% CI 10.8–25.2%; UCBT group, 10.8%, 95% CI 0.6–21.0%, P=0.325; Figures 1a and b). At last follow-up, 20 patients in the haplo-HSCT group and 4 patients in the UCBT group experienced relapse. In haplo-HSCT group, 10 patients received therapeutic DLI, and 3 patient received imatinib mesylate for treatment of cytogenetic or hematologic relapse. No patients received DLI or imatinib mesylate in the UCBT group. At the time of the last follow-up, 19 patients had died of relapse, including 15 in the haplo-HSCT group (5 treated with DLI) and 4 in the UCBT group, with a median time to death of 11 months (range, 1–24) and 6 months (range, 4–18) after transplantation, respectively.
Causes of NRM are described in Supplementary Table 2. The 1-year or 2-year cumulative incidence of NRM in the haplo-HSCT was significantly lower than that in the UCBT group (1-year NRM: haplo-HSCT group, 18.0%, 95% CI 10.8–25.2%; UCBT group, 35.1%, 95% CI 19.5–50.7%, P=0.026; 2-yeasr NRM: haplo-HSCT group, 19.9%, 95% CI 12.4–27.4%; UCBT group, 35.1%, 95% CI 19.5–50.7%, P=0.044; Figures 1c and d). Risk factor analysis is shown in Table 2.
OS and DFS
The 1-year probabilities of OS in the haplo-HSCT and UCBT groups were 73.0% (95% CI 64.7–81.3%) and 56.8% (95% CI 40.5–74.3%), respectively (P=0.048, Figure 2a). The 2-year probabilities of OS in the haplo-HSCT and UCBT groups were 66.6% (95% CI 57.8–75.4%) and 53.9% (95% CI 37.5–70.3%), respectively (P=0.099, Figure 2b).
The 1- or 2-year probabilities of DFS were comparable between haplo-HSCT and UCBT groups (1-year DFS: haplo-HSCT group, 67.6%, 95% CI 58.8–76.4%; UCBT group, 53.9%, 95% CI 37.5–70.3%, P=0.109; 2-year DFS: haplo-HSCT group, 64.0%, 95% CI 55.0–73.0%; UCBT group, 53.9%, 95% CI 37.5–70.3%, P=0.197; Figures 2c and d). Risk factor analysis is shown in Table 2.
Supplementary Table 3 reports the immune recovery data from both UCBT and haplo-HSCT recipients. The absolute counts of CD4+ and CD8+ T cells were comparable between the two groups at day 30 after HSCT, and the absolute counts of CD4+ T cells were comparable by day 90 after transplantation. However, the recovery of CD8+ T cells was faster in haplo-HSCT recipients, and the absolute counts of CD8+ T cells was significantly higher at day 90 after HSCT in the haplo-HSCT recipients than in the UCBT recipients.
Although many studies have reported that UCB and haploidentical donors are both suitable alternative sources of donor cells for children who present for HSCT without an HLA-identical sibling or URD, the present study is, to our knowledge, the first study to compare the therapeutic effects of single UCBT and unmanipulated haplo-HSCT in children with hematological malignancies. Several studies have reported that the probabilities of OS, DFS, relapse, and NRM were 40–60%, 30–50%, 20–40% and 20–44%,1,2,20 respectively, in children after single UCBT. Our study had similar findings: the 2-year probabilities of OS, DFS, relapse, and NRM were 53.9%, 53.9%, 10.8% and 35.1%, respectively, in UCBT recipients. We found that haplo-HSCT recipients had better 1-year OS, lower 1-year NRM and lower 2-year NRM rates than UCBT recipients. Therefore, it is suggested that for the children with hematologic malignancies, the therapeutic effects of haplo-HSCT might be better than that of UCBT.
In our study, haplo-HSCT recipients had a significantly lower incidence of NRM than UCBT recipients. This may be partly because of the delayed hematopoietic recovery in patients who receive UCBT. We observed that the haplo-HSCT recipients had faster neutrophil and platelet recovery rates than UCBT recipients, and their 100-day cumulative incidence of neutrophil and platelet engraftment was significantly higher than that of UCBT recipients. Kanda et al.6 also found that the neutrophil and platelet recoveries in the haplo-HSCT cohort were significantly better than that in the UCBT cohort. Thus far, several studies have reported that lower numbers of mononuclear or CD34+ cells in allografts are associated with an increased risk of engraftment failure.12 We observed that both the median mononuclear cells and median CD34+ counts were higher in haplo-HSCT recipients than in UCBT recipients. The relatively low number of progenitor cells in a single CB unit resulted in delayed hematopoietic recovery and an increased rate of infections.
Despite the use of prophylactic or pre-emptive treatments, CMV infection remains an obstacle for successful haplo-HSCT. However, we found that although the 100-day cumulative incidence of CMV antigenemia was comparable between the groups, the incidence of CMV-related interstitial pneumonia in haplo-HSCT recipients was significantly lower than that in UCBT recipients. Similarly, Lu et al.10 reported a higher 100-day cumulative incidence of CMV antigenemia in patients undergoing haplo-HSCT than that in a matched cohort (65% vs 39%, respectively), whereas the incidence of CMV-related interstitial pneumonia was the same in the two cohorts (17% vs 17%, respectively). Luo et al.21 found that when CMV is reactivated in adults, there is a significant expansion of CMV-specific CD8+ T lymphocytes (CTLCMV), which is accompanied by the recovery of CD8+ T cells. CTLCMV may proliferate and differentiate into effector memory T cells when stimulated with the CMV antigen. Thus, the recovery of CD8+ could contribute to a reduced incidence of CMV disease, even though there is a higher incidence of CMV antigenemia in haplo-HSCT recipients. In our study, we also observed that the absolute counts of CD8+ T cells in UCBT recipients were lower than that in haplo-HSCT recipients, particularly at day 90 after HSCT. We speculate that delayed early reconstitution of CD8+ T cells might contribute to the higher incidence of CMV-related interstitial pneumonia in the UCBT group. However, the immune reconstitution of children is still not well understood, and the differences of immune reconstitution between UCBT and haplo-HSCT children should be investigated further.
Severe acute GVHD was also an important cause of NRM. In this study, we found that the 100-day cumulative incidence of grade II–IV or grade III–IV acute GVHD did not differ significantly between the groups. We were able to decrease the occurrence of acute GVHD, especially that of severe acute GVHD, after haplo-HSCT with our protocol,7,10 which included a combination of the G-CSF-primed BM harvest and G-CSF-mobilized peripheral blood stem cell harvest as the source of stem cell grafts as well as the addition of antithymocyte globulin to the conditioning regimen as prophylaxis for GVHD. Other studies also reported the excellent results of unmanipulated haplo-HSCT. Di Bartolomeo et al. 22 reported that the unmanipulated, G-CSF–primed BMT from haploidentical family donor provided very encouraging results (III–IV acute GVHD at 100 days: 5%; NRM at 3 years: 36%). Raiola et al.23 and Luznik et al.24 also reported that BMT from haploidentical donors with post-transplantation high-dose CY allowed for acceptable NRM and GVHD in patients with hematologic malignancies. The development of unmanipulated haplo-HSCT, in particular posttransplantation high-dose CY, might hold promise to further reduce NRM and GVHD.
However, we found that the cumulative incidence of relapse did not differ significantly between the haplo-HSCT and UCBT groups. This unexpected finding may well suggest that the GVL effects of UCBT might not be weaker than that of haplo-HSCT. On the other hand, although transplant techniques greatly improved, it is generally difficult to overcome the refractory nature of some high-risk hematologic malignances. Lastly, the number of UCBT recipients enrolled in our study was relatively small, making it more difficult to find significant differences in the comparative analysis with haplo-HSCT recipients. Therefore, we were temporarily unable to observe the benefits of relapse prevention in haplo-HSCT recipients.
The major limitation of this study is the relatively small sample size of the study group, in particular for the UCBT group. We observed that the curves of OS or DFS showed inferior outcome of UCB group; however, the differences were not statistically significant, which may be partly due to the small sample size. Thus, it would be premature to derive conclusions regarding the superiority of haplo-HSCT over UCBT in children with hematologic malignancies. In addition, although a matched-pair analysis was designed, there was a significant difference of age between the two groups. Several studies have found that age might be not the risk factor for poor transplant outcomes,4,25 and in our study, age was also not associated with the transplant outcomes in multivariate analysis. Nevertheless, we still could not completely exclude the influence of age. In the future, prospective multicenter studies might further confirm our results. Lastly, none of the children in our study received double UCBT. It is important to see whether the improved outcomes of haplo-HSCT will be confirmed in the trials that compare haplo-HSCT and double UCBT.
Our results show that compared with single UCBT, unmanipulated haplo-HSCT can improve the outcomes of children with hematologic malignances. However, our results require further support from multicenter and large-scale studies.
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We thank Editage for providing editorial assistance. This work was supported by the Beijing Municipal Science and Technology Program (Grant No. Z111107067311070) and the Key Program of National Natural Science Foundation of China (Grant No. 81230013).
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on Bone Marrow Transplantation website
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Mo, X., Zhao, X., Liu, D. et al. Umbilical cord blood transplantation and unmanipulated haploidentical hematopoietic SCT for pediatric hematologic malignances. Bone Marrow Transplant 49, 1070–1075 (2014). https://doi.org/10.1038/bmt.2014.109
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