Graft-versus-host Disease

Clinical separation of cGvHD and GvL and better GvHD-free/relapse-free survival (GRFS) after unrelated cord blood transplantation for AML

Abstract

Few studies have presented a comparison of myeloablative cord blood transplantation (CBT) and HLA-identical sibling hematopoietic cell transplantation (HCT) for AML in a disease-specific analysis, and the evaluation of GvHD-free and relapse-free survival (GRFS) in AML patients after unrelated CBT has not been reported. A total of 162 consecutive AML patients receiving intensified myeloablative unrelated CBT (n=107) or allogeneic PBSC transplantation (allo-PBSCT) or bone marrow transplantation (BMT) from an HLA-identical sibling donor (n=55) were investigated. Neutrophil or platelet engraftment was slower in the CBT cohort compared with that in the allo-PBSCT/BMT cohort. The incidence of grade II–IV or grade III–IV acute GvHD (aGvHD) and transplant-related mortality (TRM) were not significantly different in the two cohorts. Compared with the allo-PBSCT/BMT cohort, the CBT cohort had a significantly lower rate of chronic GvHD (cGvHD) (13.7% vs 28.3%; P=0.047) or extensive cGvHD (9.9% vs 24.1%; hazard ratio (HR)=2.06, P=0.039). The incidence of relapse at 5 years in the CBT cohort was significantly lower than that in the allo-PBSCT/BMT cohort (15.3% vs 36.1%; HR=4.62, P=0.009). The probabilities of overall survival and leukemia-free survival were similar between the two cohorts. The adjusted 5-year probability of GRFS was higher after CBT than that after allo-PBSCT/BMT (55.4% vs 39.2%; HR=1.63, P=0.042). The present study suggests that, for AML patients, intensified myeloablative unrelated CBT is associated with less cGvHD and a lower risk of relapse. In addition, these patients do not experience excessive TRM or severe aGvHD that translates into better GRFS compared with those patients who undergo HLA-identical sibling allo-PBSCT/BMT; this observation may reflect the clinical separation between cGvHD and GvL within our CBT protocol.

Introduction

Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising curative approach for treating high-risk or relapsed/refractory AML. Unrelated cord blood transplantation (CBT) is increasingly being employed as an alternative transplant strategy for AML patients who lack a related or unrelated donor with an identical HLA type. Cord blood (CB) has some potential advantages, including the absence of donor risk, rapid accessibility and less rigorous requirement for HLA compatibility. Recently, reduced-intensity conditioning followed by CBT has been conducted for high-risk AML patients to decrease the early transplant-related mortality (TRM),1, 2 but the incidence of relapse was high (nearly 50%), and the long-term survival was very poor. New strategies should be further investigated to improve the antileukemic effect after CBT. We have reported that myeloablative CBT can result in improved survival and decreased relapse rates in adult or pediatric recipients with hematologic malignancies3, 4 compared with transplants from HLA-matched sibling donors (MSD); however, few studies have presented a comparative analysis of myeloablative CBT and allo-HCT from MSD for AML in a disease-specific manner. GvHD-free and relapse-free survival (GRFS) is a novel composite end point of allo-HCT, and takes into account severe acute GvHD (aGvHD), extensive chronic GvHD (cGvHD), TRM and relapse, and represents real recovery after allo-HCT.5 However, the evaluation of GRFS in AML patients after unrelated CBT has not yet been reported. In this disease-specific study, we retrospectively analyzed the outcomes of AML patients receiving unrelated CBT with intensified myeloablative conditioning compared with those patients receiving transplantation from MSD, with an emphasis on transplant-related complications (severe aGvHD and extensive cGvHD), relapse and GRFS.

Patients and methods

Patient eligibility

A retrospective review was performed on AML patients receiving allo-transplantation at Anhui Provincial Hospital from November 2002 to June 2015. Included in this analysis were AML patients undergoing unrelated CBT or HLA-identical sibling allogeneic PBSC transplantation (allo-PBSCT) or bone marrow transplantation (BMT) with myeloablative conditioning. A total of 162 consecutive AML patients receiving unrelated CBT (n=107; 72 were previously reported6) or HLA-identical sibling allo-PBSCT/BMT (n=55; 40 received PBSCs, 11 received PBSCs and BM and 4 received BM) during the study period were enrolled. All of the 162 AML patients had one or more of the following clinical characteristics: patients in CR1 (n=109, 67.3%) with high-risk cytogenetic or molecular aberrations (inv(3)(q21q26.2) or t(3;3)(q21;q26.2), t(6;9)(p23;q34), 11q23 abnormalities (mixed lineage leukemia (MLL) rearrangements), −5 or del(5q), −7 or del(7q), complex karyotype, normal cytogenetics with FLT3 internal tandem duplication mutation), a previous history of myelodysplastic syndrome or minimal residual disease persistence before transplantation; CR2 or higher (n=32, 19.8%); or relapsed or refractory disease status (n=21, 12.9%). The baseline patient and disease-related characteristics are demonstrated in Table 1, and there were no significant differences between the two groups in terms of patient age, sex, disease risk at first diagnosis or disease stage during transplant.

Table 1 Patients and transplant characteristics

Transplant characteristics

MSD was the first selection for allo-HCT. Unrelated CB was chosen if an MSD was unavailable, or if there was not sufficient time to wait for an unrelated donor because of leukemia progression. CB units were serologically matched for at least 4 of 6 HLA loci and the target total nucleated cell and CD34+ cell count were 3 × 107/kg and 1.2 × 105/kg of recipient weight before freezing, respectively. Out of 107 patients, 97 (90.7%) received single-unit CBT. The transplantation procedures used have been reported previously.3, 6 All patients in the CBT cohort received an intensified myeloablative conditioning regimen that included BUCY2 (busulfan (0.8 mg/kg IV every 6 h, day −7 to day −4), cyclophosphamide ( 60 mg/kg daily, day −3 to day −2)) plus high-dose cytarabine (HDAC, 2.0 g/m2 every 12 h, day −9 to day −8) (n=45, 42.1%) or fludarabine (30 mg/m2 daily, day −8 to day −5) (n=15, 14.0%) (age <14 years) or TBICY (TBI, 12 Gy in 4 fractions, day −7 to day −6), cyclophosphamide (60 mg/kg daily, day −3 to day −2)) plus HDAC (2.0 g/m2 every 12 h, day −5 to day −4) (n=47, 43.9%) (age 14 years). G-CSF was used at 5 μg/kg for 3 consecutive days beginning at 1 day before HDAC administration by daily SC injection. The conditioning treatment for the allo-PBSCT/BMT cohort was BUCY2 (n=52, 94.5%) or TBICY (n=3, 5.5%), and 7 patients (12.7%) received HDAC. For patients at high risk of central nervous system recurrence (WBC 100 × 109/l at first diagnosis or CR2 status or relapsed or refractory disease) or patients with a history of central nervous system leukemia, carmustine (250 mg/m2) was administered on the first day of the conditioning regimen either in the CBT cohort (n=50, 46.7%) or in the allo-PBSCT/BMT cohort (n=24, 43.6%). Cyclosporine and mycophenolate mofetil were used for GvHD prophylaxis as previously described.3, 6 The transplant protocols were approved by the ethics committee of Anhui Provincial Hospital.

Statistical analyses

Engraftment, GvHD, TRM, relapse, overall survival (OS) and leukemia-free survival (LFS) were defined according to previously published criteria.7, 8, 9 Patient-, disease- and transplant-related variables between the CBT and allo-PBSCT/BMT groups were measured using χ2 test (categorical variables) or Mann–Whitney U-test (continuous variables). The variables chosen for analysis were age, sex, disease risk at first diagnosis, disease stage during transplant, recipient CMV serology before transplant, HLA match, ABO compatibility, conditioning regimens, GvHD prophylaxis, total nucleated cell dose and CD34+ cell dose. The probabilities of neutrophil and platelet engraftment, aGvHD, cGvHD, TRM and relapse were generated by the cumulative incidence function method, taking into account competing risks. The probabilities of OS and LFS were generated by the Kaplan–Meier method. Death from any cause was regarded as an end point for analysis of OS, and relapse or death was regarded as an end point for analysis of LFS. The Cox proportional hazards model was applied to describe outcomes (engraftment, GvHD, TRM, relapse, OS, LFS and GRFS) between the CBT and MSD cohorts; and age, disease risk at first diagnosis (standard or intermediate risk vs high risk), disease stage before transplant (CR1 vs CR2 or higher vs no remission) and transplant conditioning were considered in the multivariate models. For analysis of GRFS, the end points were defined as grade III–IV aGvHD, extensive cGvHD, relapse or death. The adjusted probability of GRFS was calculated with selective variables in the final multivariate analysis (age, graft source, disease risk at first diagnosis and disease stage before transplant). All of these analyses were conducted using R statistical software (R Foundation for Statistical Computing, Vienna, Austria; version 2.13.0). Differences with Р<0.05 were considered significant.

Results

Engraftment

STR-PCR was conducted in all patients. In all, 100 patients (93.5%) from the CBT cohort and 55 patients (100%) from the allo-PBSCT/BMT cohort had full donor chimerism. The cumulative incidence of neutrophil engraftment at day 42 in the CBT cohort was 94.2% (95% confidence interval (CI), 87.5–97.3%) and 100% in the allo-PBSCT/BMT cohort (P=0.56). The cumulative incidence of platelet engraftment at day 60 was 73.5% (95% CI, 63.4–80.8%) in the CBT cohort and 100% in the allo-PBSCT/BMT cohort (P<0.001); at day 100, the incidences were 82.5% (95% CI, 73.3–88.6%) and 100% (P<0.001), respectively. Median times to neutrophil and platelet engraftment were 17 days (range: 11–42) and 37 days (range: 17–140) for recipients of CB, and 11 days (range: 10–19) and 14.5 days (range:11–25) for recipients of MSD, respectively (P<0.001, <0.001; Table 1).

GvHD

At 100 days after transplantation, 29 recipients in the CBT group and 11 recipients in the allo-PBSCT/BMT group developed grade II–IV aGvHD, with severe aGvHD (grade III–IV) observed in 16 and 6 patients from each group, respectively. In a univariate analysis, the day-100 cumulative incidence of grade II–IV aGvHD in the CBT cohort was 28.7% (95% CI, 19.3-37.0%) compared with 19.6% (95% CI, 10.5-28.1%) in the allo-PBSCT/BMT cohort (P=0.12; Table 1), and the corresponding rates of severe aGvHD (grade III–IV) were 16.8% (95% CI, 9.2–23.8%) and 9.9% (95% CI, 3.8–16.4%) in each cohort (P=0.20), respectively (Figure 1a). In a multivariate analysis (Table 2), the risk of grade II–IV or grade III–IV aGvHD between the two cohorts showed no significant difference (hazard ratio (HR)=0.68; 95% CI, 0.33–1.75; P=0.22; HR=0.79; 95% CI, 0.36–2.38; P=0.68).

Figure 1
figure1

Cumulative incidence of grade III–IV acute GvHD and extensive chronic GvHD. The cumulative incidence of grade III–IV aGvHD at day 100 in the CBT cohort was 16.8% (95% CI, 9.2–23.8%) compared with 9.9% (95% CI, 3.8–16.4%) in the allo-PBSCT/BMT cohort (P=0.20) (a), and the corresponding rates of extensive cGvHD were 9.9% (95% CI, 2.5–16.8%) and 24.1% (95% CI, 10.5–35.7%) (P=0.023) (b). A full color version of this figure is available at the Bone Marrow Transplantation journal online.

Table 2 Multivariate analyses of transplant outcomesa

For patients who survived for at least 100 days after transplantation, 10 patients in the CBT cohort and 13 patients in the allo-PBSCT/BMT cohort developed limited or extensive type cGvHD.

The cumulative incidence of cGvHD was significantly lower in the CBT cohort when compared with that in the allo-PBSCT/BMT cohort (13.7% (95% CI, 5.3–21.3%) vs 28.3% (95% CI, 13.8–40.3%)) (P=0.047) and extensive cGvHD (9.9% (95% CI, 2.5–16.8%) vs 24.1% (95% CI, 10.5–35.7%)) (P=0.023) (Figure 1b). A significantly lower incidence of extensive cGvHD was also observed in the CBT cohort from the multivariate analysis (HR=2.06; 95% CI, 0.92–4.61; P=0.039; Table 2).

TRM and relapse

Thirty-one recipients in the CBT cohort died of transplant-related complications, including refractory severe aGvHD (n=9, 29.1%), pulmonary bacterial and/or fungal infection (n=16, 51.6%), CMV disease (n=5, 16.1%) and intracranial hemorrhage (n=1, 3.2%). Twelve recipients in the allo-PBSCT/BMT cohort died because of refractory severe aGvHD (n=3, 25.0%), pulmonary bacterial and/or fungal infection (n=5, 41.7%), intracranial hemorrhage or cerebral infarction (n=2, 16.7%), sinusoidal obstruction syndrome (n=1, 8.3%) and multiple organ failure (n=1, 8.3%). Among the recipients of CB, the 6-month and 5-year cumulative incidences of TRM were 24.3% (95% CI, 16.6–32.8%) and 27.4% (95% CI, 19.2–36.2%) compared with 12.7% (95% CI, 5.5–23.6%) and 20.3% (95% CI, 10.7–31.9%) in the recipients of MSD, respectively (Figure 2). There was no significant difference in TRM between the two cohorts in univariate analysis (P=0.24) or multivariate analysis (HR=0.75; 95% CI, 0.42–1.52; P=0.43; Table 2).

Figure 2
figure2

Cumulative incidences of TRM and relapse. The 5-year cumulative incidence of TRM was 27.4 (95% CI, 19.2–36.2%) in the CBT group compared with 20.3% (95% CI, 10.7–31.9%) in the allo-PBSCT/BMT group (P=0.24). The 5-year relapse rate after CBT was 15.3% (95% CI, 8.9–22.4%), and this was significantly lower than that after allo-PBSCT/BMT (36.1% (95% CI, 18.3–54.3%)) (P=0.006). A full color version of this figure is available at the Bone Marrow Transplantation journal online.

Eleven recipients in the CBT cohort and 16 recipients in the allo-PBSCT/BMT cohort suffered leukemia relapse. The 5-year cumulative incidence of relapse was 15.3% (95% CI, 8.9–22.4%) in the CBT recipients and 36.1% (95% CI, 18.3–54.3%) in the allo-PBSCT/BMT recipients. The incidence of relapse in the CBT cohort was significantly lower than that in the allo-PBSCT/BMT cohort according to univariate analysis (P=0.006; Figure 2) or multivariate analysis (HR=4.62; 95% CI, 1.71–8.67; P=0.009; Table 2).

OS, LFS and GRFS

Among the patients still alive, the median follow-up time was 42.3 months (range, 10–150) for the CBT cohort and 51.5 months (range, 12–120) for the allo-PBSCT/BMT cohort (P=0.36). The estimated OS and LFS were similar between two cohorts. The 5-year OS was 66.4% (95% CI, 56.4–74.6%) for CBT patients and 57.8% (95% CI, 42.9–70.1%) for allo-PBSCT/BMT patients (P=0.78; Figure 3a); the 5-year LFS was 62.3% (95% CI, 52.3–70.8%) for CBT patients and 50.9% (95% CI, 35.7–64.2%) for allo-PBSCT/BMT patients (P=0.43; Figure 3b). No significant difference in OS or LFS was observed between the two cohorts in multivariate analysis (HR=1.13; 95% CI, 0.65–1.89; P=0.71; HR=1.38; 95% CI, 0.82–2.34; P=0.38; Table 2).

Figure 3
figure3

Probabilities of OS and LFS. The 5-year OS was 66.4% (95% CI, 56.4–74.6%) for CBT patients and 57.8% (95% CI, 42.9–70.1%) for allo-PBSCT/BMT patients (P=0.78) (a); the 5-year LFS was 62.3% (95% CI, 52.3–70.8%) and 50.9% (95% CI, 35.7–64.2%), respectively (P=0.43) (b). A full color version of this figure is available at the Bone Marrow Transplantation journal online.

Combining GRFS-defining events (grade III–IV aGvHD, extensive cGvHD, relapse or death), the adjusted 5-year probability of GRFS for recipients in the CBT cohort was 55.4% (95% CI, 45.3–64.4%), significantly higher than that in the MSD cohort (39.2%; 95% CI, 25.5–52.7%; HR=1.63; 95% CI, 1.01–2.62; P=0.042; Figure 4 and Table 2).

Figure 4
figure4

Adjusted probabilities of GRFS. In multivariate analysis, the adjusted 5-year probabilities of GRFS for patients in the CBT cohort was 55.4% (95% CI, 45.3–64.4%), and this was significantly higher than that in the allo-PBSCT/BMT cohort (39.2%; 95% CI, 25.5–52.7%; HR=1.63; 95% CI, 1.01–2.62; P=0.042). Adjusted probability of GRFS was calculated with consideration of the variables in the final multivariate models (age, disease risk at first diagnosis, disease stage in transplant and transplant conditioning). A full color version of this figure is available at the Bone Marrow Transplantation journal online.

Discussion

Few studies have specifically explored the efficacy or safety of transplant of CB compared with that of MSD for AML patients. In this study, we demonstrated that unrelated CBT had similar long-term survival (OS or LFS), similar incidence of severe aGvHD and TRM, a lower incidence of cGvHD and a reduced relapse rate compared with allo-PBSCT/BMT from MSD. The novel composite end point, GRFS, reflects the main complications of allo-HCT and represents the real recovery following allo-HCT. Holtan et al.5 first identified the value of GRFS and found that HLA-MSD BMT resulted in a better GRFS than did CBT or HLA-MSD PBSCT from a cohort of 907 recipients. Konuma et al.10 analyzed long-term GRFS based on data from 256 hematologic malignancies that underwent myeloablative allo-HCT, and the results indicated that long-term GRFS after HSCT was similar among recipients of unrelated CB or MSD. The data from the Donor/Source Working Group of the Japan Society for HSCT also showed that11 for patients 50 years old, CBT led to GRFS that was similar to that achieved with BMT or PBSCT. However, in this disease-specific study, we found that AML patients receiving unrelated CBT exhibited GRFS that was superior to that from patients who received HLA-matched sibling allo-PBSCT/BMT. GRFS takes into account severe aGvHD or extensive cGvHD, TRM and relapse, and therefore the low incidence of extensive cGvHD and the reduced incidence of relapse without excessive TRM and severe aGvHD likely contributed to the superior GRFS in the CBT cohort.

Our results indicated a very low incidence of cGvHD or extensive cGvHD with CBT, despite the same GvHD prophylaxis protocol compared with that of sibling allo-PBSCT/BMT. Extensive cGvHD, as a clinically meaningful composite end point for GRFS, could increase the burden of morbidity and mortality and result in an unsuccessful HSCT;12 a low incidence of cGvHD represents a good transplant performance status and better quality of life.13, 14 We previously reported that patients off immunosuppressive treatment or returning to school or work were significantly higher after unrelated CBT4 compared with those after sibling HCT; this illustrated that CBT survivors had a better quality of life and experienced real recovery after transplantation. Many clinical findings demonstrated that previous occurrence of grade II–IV aGvHD was an independent risk factor for cGvHD (especially for extensive cGvHD).15, 16, 17 This may be true for patients with allo-PBSCT/BMT in our present study (19.6% with grade II–IV aGvHD and 24.1% with extensive cGvHD). However, for CBT patients, the relatively high incidence of grade II–IV aGvHD or severe aGvHD did not translate into a high incidence of cGvHD (28.7% with grade II–IV aGvHD and 9.9% with extensive cGvHD). This phenomenon implied that the pathophysiology of cGvHD development in CBT recipients was distinct from that in PBSCT/BMT recipients. Antithymocyte globulin (ATG) use could lead to a lower incidence of extensive cGvHD in unrelated or haploidentical HCT.18, 19 However, this is not true for unrelated CBT. In this study, we identified that cGvHD or extensive cGvHD was significantly lower in the CBT cohort than in the allo-PBSCT/BMT cohort, even though ATG was omitted in the conditioning regimen. Our previous data also indicated that20 in patients undergoing unrelated CBT, ATG-containing regimens had no impact on aGvHD or cGvHD compared with patients who did not receive ATG, suggesting that CBT patients cannot obtain additional protection from ATG use.

The current study demonstrated that compared with allo-PBSCT/BMT from MSD, unrelated CBT led to a significantly lower incidence of disease relapse, although more CBT patients presented with high-risk features (81.3% in the CBT cohort vs 58.2% in the allo-PBSCT/BMT cohort). Clinical studies suggested that unrelated CBT, especially in the setting of a T cell-replete HLA-mismatched graft, might decrease leukemia relapse. Our previous data also suggested that the long-term LFS after CBT could be attributed to the durable allogeneic immune reactions that continue to suppress leukemia progression after transplantation,3, 6, 21 especially for primary refractory or relapsed disease22 because of the fact that high-dose chemotherapy was usually ineffective at prolonging survival. These findings supported the hypothesis that a more potent GvL effect may be achieved after CBT. Hiwarkar et al.23 recently demonstrated that HLA-mismatch CB T cells mediated superior antitumor responses compared with T cells from donor PB using an experimental model, and this provocative study indicated that CB T cells were intrinsically more effective at GvL. In the present study, more recipients with HLA disparity (85% with 1- or 2-antigen mismatch) and the omission of ATG from the conditioning regimen (T cell replete) could both contribute to the robust GvL effect after CBT. On the other hand, more patients in the CBT cohort received TBICY-based conditioning (43.9%) or HDAC as part of their conditioning regimens (86%). The treatment advantages of TBI-based regimens include no cross-resistance to chemotherapy regimens, dose distribution regardless of vascular supply and effective treatment of sanctuary sites.24 We hypothesize that myeloablative conditioning (TBICY or BUCY2) combined with HDAC could lead to more effective disease control, especially for minimal residual disease-positive patients, or refractory or relapsed patients, and the cytotoxic effect of HDAC on myeloid leukemic cells would be enhanced by concomitant use of G-CSF. HDAC can eradicate residual leukemia cells as a result of active uptake into the target cells, and it can also kill the tumor cells in sanctuary sites through penetrating the blood–organ barriers. Previous studies have verified that myeloablative conditioning combined with HDAC could lead to more effective disease control for CBT patients.25, 26 Arai et al.27 recently performed a comparative analysis to investigate the efficiency of HDAC added to TBICY in CBT for AML/myelodysplastic syndrome, and found that the addition of HDAC significantly improved OS (53.0% vs 41.3% at 3 years) by suppressing relapse; however, for AML/myelodysplastic syndrome patients who underwent myeloablative PBSCT/BMT, HDAC could not provide an additional antileukemic effect but instead lead to an inferior OS (45.3% vs 58.8% at 3 years).28

In summary, this comparison suggests that for AML patients, unrelated CBT is associated with a similar incidence of severe aGvHD and TRM but less cGvHD (especially extensive cGvHD) and a lower risk of relapse that translates into better GRFS compared with HLA-matched sibling allo-PBSCT/BMT. This observation reflects the clinical separation of cGvHD and the GvL effect within our CBT protocol. However, there are some limitations to this study. First, this was a nonprospective and nonrandomized study, and the patient number in the allo-PBSCT/BMT group was relatively small. Second, some patient characteristics were not uniform between the two groups, such as the fact that the patients in the CBT cohort were slightly younger (although the difference did not reach statistical significance), and more patients in the CBT cohort had high-risk features, including greater disease states of CR2 or higher or a failure to achieve remission. Third, there are mixed pediatric and adult patients enrolled in this study, and the upper limited age in both cohorts was nearly 50 years that is relatively young for an adult population, and hence this analysis cannot extrapolated to other transplant centers that treat older patients.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81570159 and 81470350), Anhui Provincial Natural Science Foundation of China (No. 1608085MH181) and Anhui Provincial Public Welfare Technology Application Research linkage project in 2015 (No. 1501ld04020).

Author contributions

C-CZ and Z-MS designed the study, performed the research, provided and analyzed the data. C-CZ wrote the paper. B-LT, X-YZ, X-HZ, LZ, L-QG and H-LL provided data, edited the paper and contributed to the analysis of research.

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Correspondence to Z-M Sun.

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Zheng, C., Zhu, X., Tang, B. et al. Clinical separation of cGvHD and GvL and better GvHD-free/relapse-free survival (GRFS) after unrelated cord blood transplantation for AML. Bone Marrow Transplant 52, 88–94 (2017) doi:10.1038/bmt.2016.182

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