Abstract Allogeneic stem cell transplantation is an effective treatment for high-risk myeloid malignancies, but relapse remains the major post-transplantation cause of treatment failure. Alloreactive ...natural killer (NK) cells mediate a potent antileukemic effect and may also enhance engraftment and reduce graft-versus-host disease (GVHD). Haploidentical transplantations provide a setting in which NK cell alloreactivity can be manipulated, but they are associated with high rates of GVHD. We performed a phase I study infusing escalating doses of NK cells from an HLA haploidentical–related donor—selected for alloreactivity when possible—as a component of the preparative regimen for allotransplantation from a separate HLA-identical donor. The goal of infusing third-party alloreactive NK cells was to augment the antileukemic effect of the transplantation without worsening GVHD and, thus, improve the overall outcome of hematopoietic transplantation. Twenty-one patients with high-risk acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelogenous leukemia refractory or beyond first remission received a preparative regimen with busulfan and fludarabine followed by infusion of apheresis-derived, antibody-selected, and IL-2–activated NK cells. Doses were initially based on total nucleated cell (TNC) content and later based on CD56+ cells to reduce variability. CD56+ content ranged from .02 to 8.32 × 106 /kg. IL-2, .5 × 106 units/m2 subcutaneously was administered daily for 5 days in the final cohort (n = 10). CD3+ cells in the NK cell product were required to be < 105 /kg. Median relapse-free, overall, and GVHD-free/relapse-free survival for all patients enrolled was 102, 233, and 89 days, respectively. Five patients are alive, 5 patients died of transplantation-related causes, and 11 patients died of relapse. Despite the small sample size, survival was highly associated with CD56+ cells delivered ( P = .022) and development of ≥ grade 3 GVHD ( P = .006). There were nonsignificant trends toward higher survival rates in those receiving NK cells from KIR ligand–mismatched donors and KIR-B haplotype donors. There was no association with disease type, remission at time of transplantation, or KIR content. GVHD was not associated with TNC, CD56+ , or CD3+ cells infused in the NK cell product or the stem cell product. This trial demonstrates a lack of major toxicity attributable to third-party NK cell infusions delivered in combination with an HLA-compatible allogeneic transplantation. The infusion of haploidentical alloreactive NK cells was well tolerated and did not interfere with engraftment or increase the rate of GVHD after allogeneic hematopoietic transplantation. Durable complete remissions occurred in 5 patients at high risk for disease recurrence. This approach is being further developed in a phase I/II trial with ex vivo–expanded NK cells to increase the NK cell dose with the objective of reducing relapse and improving the outcome of allogeneic hematopoietic transplantation for AML/MDS.
At our center, we observed a series of patients who developed transudative refractory ascites secondary to noncirrhotic, non-veno-occlusive disease (VOD)–related portal hypertension after allogeneic ...hematopoietic stem cell transplantation (allo-HSCT). Patients were considered to have idiopathic portal hypertension-related refractory ascites (IRA) if they developed ascites secondary to intrahepatic portal hypertension (serum ascites albumin gradient ≥1.1 g/dL or hepatic venous pressure gradient HVPG >5 mm Hg), but did not meet the clinical criteria for classical VOD/sinusoidal obstructive syndrome (SOS) and did not have any alternate etiology of portal hypertension. From our institutional database, we identified 40 patients who developed IRA after allo-HSCT between 2004 and 2018. The patients' median age at the time of allo-HSCT was 54 years (range, 21-73 years). The median time to development of IRA after allo-HSCT was 80 days (range, 16-576 days). The median number of paracentesis was 3 (range, 1-11), and 15 (38%) patients had an intraperitoneal catheter placed for continued drainage of the rapidly accumulating ascites. Portal pressures were measured in 19 patients; 6 (15%) had moderate portal hypertension (HVPG 6-9 mm Hg), and 13 (33%) had severe portal hypertension (HVPG ≥ 10 mm Hg). Liver biopsy was performed in 24 patients. None of the patients met the criteria for classical VOD/SOS (clinical/histological) or cirrhosis (histological). The cumulative incidence of nonrelapse mortality was 63%, and the median survival duration after the development of the IRA was 7 months (range, 0.8-125.6 months). IRA is a poorly understood and often fatal complication of allo-HSCT.
•IRA is an unrecognized fatal complication of allo-HSCT not reported before.•Incidence of IRA is 1% and IRA is fatal in 63% of cases.
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Background: We previously showed that PTCy/Tac ± MMF is associated with a significant reduction in the rate of chronic graft-versus-host disease (cGvHD) as compared to Tac/MTX after HLA-matched ...sibling (MSD) but not after HLA-matched unrelated (MUD) donor stem cell transplant (SCT). Notably, ATG was used with Tac/MTX in MUD but not in MSD. Transplant Cell Ther. 2022;28(10):695 We aimed to further elucidate the epidemiology of cGvHD with the use of PTCy/Tac by comparing the impact of Tac/MTX vs PTCy/Tac ± MMF on de novo and progressive/relapsing cGvHD. Methods: Recipients of a MSD (Tac/MTX no ATG, or PTCy-based) or MUD (Tac/MTX with ATG, or PTCy-based) peripheral blood SCT between 2015-21 at our institution were eligible. To evaluate the impact of prophylaxis on the incidence of de novo and progressive/relapsing cGvHD, we performed two separate landmark analyses starting 3 months (mo) post-SCT among patients who had not and those who had been diagnosed with acute GvHD (aGvHD) within 3 mo post-SCT, respectively. Patients who died or experienced relapse of malignancy (n=135) or were diagnosed with cGvHD within 3 mo post-SCT (n=13) were excluded from the landmark analyses. There was no difference in the rate of early death/relapse or cGvHD by prophylaxis. Results: 1040 patients met the eligibility criteria. Median follow-up in survivors was 28 mo (IQRT: 18, 50). The cumulative incidence (CumInc) of cGvHD in the Tac/MTX, PTCy/Tac without MMF, and PTC/Tac with MMF groups was 39% (34-45, reference), 20% (14-29, p<0.001) and 20% (13-30, p=0.003) respectively in MSD; and 23% (18-30, reference), 17% (12-26; p=0.2), and 19% (14-26; p=0.6) respectively in MUD. Consistent with our previous findings, within the PTCy/Tac group, MMF was not associated with the overall rate of cGvHD in MSD (HR=1.2, 95% CI 0.6-2.1, p=0.6) or MUD (HR=1.3, 95% CI 0.7-2.2, p=0.4). However, in the current study, stratified analyses performed to evaluate the impact of prophylaxis on the risk of de novo vs progressive/relapsing cGvHD revealed a potential role for MMF in the development of de novo cGvHD. Subsequent results are presented separately for the de novo and progressive/relapsing cGvHD risk cohorts (Table). The de novo cGvHD risk cohort included patients (N=442) who had not been diagnosed with aGvHD within 3 mo post-SCT. AML / MDS (60%) and CML / MPD (16%) were the most common diagnoses. 124 cases of cGvHD were diagnosed 3 -36 mo post-SCT with a CumInc of32% (27-37). In multivariate analysis (MVA), compared to Tac/MTX, the use of PTCy/Tac without MMF (HR=0.3, 95% CI 0.2-0.6, p<0.001) was associated with a significant reduction in the incidence of cGvHD. Such reduction was not observed (Figure) with PTCy/Tac with MMF (HR vs Tac/MTX=1.0, 95% CI 0.6-1.5, p=0.9). Additional independent predictors were myeloablative conditioning (HR=1.9, 95% CI 1.3-2.9, p=0.001) and MSD (HR=1.5, 95% CI 1.2-2.6, p=0.003). Notably, progression-free survival (PFS) was similar in PTCy/Tac/MMF (univariate HR: 0.8, 95% CI 0.5-1.4, p=0.4) vs PTCy/Tac. The progressive/relapsing cGvHD risk cohort included patients (N=450) who had been diagnosed with grade 1 (27%), 2 (59%) or 3-4 (14%) aGvHD within 3 mo post-SCT. AML / MDS (64%) and CML / MPD (14%) were the most common diagnoses. 109 cases of cGvHD were diagnosed 3 -36 mo post-SCT with a CumInc of 28% (24-33). In MVA analysis, the impact of prophylaxis differed by donor type. As compared with Tac/MTX, PTCy/Tac ± MMF was associated with significantly lower rate of progressive/relapsing cGVHD in MSD (HR=0.2, 95% CI 0.1-0.4, p<0.001) but not in MUD (HR=0.6, 95% CI 0.4-1.1, p=0.09). This may be related to the use of ATG with Tac/MTX in MUD which was not used in MSD. HCT-CI ≥3 was the only other significant predictor of cGvHD (HR=0.6, 0.4-0.9, p=0.03). PFS was similar in PTCy/Tac ± MMF vs Tac/MTX in MSD (univariate HR: 0.8, 95% CI 0.5-1.3, p=0.3) or MUD (univariate HR: 0.8, 95% CI 0.5-1.2, p=0.3). Conclusions: PTCy/Tac ± MMF prophylaxis slows the development of progressive/relapsing cGvHD in MSD vs (Tac/MTX no ATG), but not in MUD (vs Tac/MTX with ATG). The addition of MMF to PTCy/Tac (vs PTCy/Tac) has no significant impact on the risk of progressive/relapsing cGVHD in MSD or MUD; but is associated with a higher risk of de novo cGvHD in MSD and MUD. Our data suggest that multi-center studies are warranted to determine whether MMF should be excluded from cGvHD prevention regimens in the HLA-matched donor setting with PTCy- based GvHD prophylaxis.
The optimal conditioning regimen for older patients with acute myeloid leukemia (AML) remains unclear. In this study, we compared outcomes of AML patients >60 years of age undergoing allogenic ...hematopoietic stem cell transplantation at our institution. All 404 consecutively treated patients received 1 of the following conditioning regimens: (1) fludarabine+melphalan 100 mg/m2 (FM100), (2) fludarabine+melphalan 140 mg/m2 (FM140), (3) fludarabine+IV busulfan AUC ≥ 5000/d × 4 d (Bu≥20000), and (4) fludarabine+IV busulfan AUC 4000/d × 4 d (Bu16000). A propensity score analysis (PSA) was used to compare outcomes between these 4 groups. Among the 4 conditioning regimens, the FM100 group had a significantly better long-term survival with 5-year progression-free survival of 49% vs 30%, 34%, and 23%, respectively. The benefit of the FM100 regimen resulted primarily from the lower nonrelapse mortality associated with this regimen, an effect more pronounced in patients with lower performance status. The PSA confirmed that FM100 was associated with better posttransplantation survival, whereas no significant differences were seen between the other regimen groups. In summary, older patients with AML benefited from a reduced-intensity conditioning regimen with lower melphalan doses (FM100), which was associated with better survival, even though it was primarily used in patients who could not receive a more intense conditioning regimen.
•Reduced-intensity melphalan-based conditioning provides the best survival in older AML patients undergoing stem cell transplantation.•A more intense myeloablative conditioning regimen does not provide a survival benefit in these patients.
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•Myeloablative pharmacokinetic-guided i.v. busulfan is safe in older myelofibrosis patients.•It reduced relapse without increasing NRM even in older patients.•Intermediate 2 DIPSS-plus risk has ...better outcomes than high-risk disease.
Optimal conditioning regimens for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplant are not known. Likewise, the role of dose intensity is not clear.
We conducted a nonrandomized, prospective, phase II trial using low-dose, later escalated to high-dose (myeloablative conditioning), busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to age 74 years. The first 15 patients received i.v. busulfan 130 mg/m2/day on days –3 and –2 (“low dose”); 31 patients received high-dose conditioning, either 100 mg/m2/day (days –5 to –2; n = 4) or pharmacokinetic-guided area under the curve of 4000 μmol/min (days –5 to –2; n = 27). The primary endpoint was day 100 nonrelapse mortality (NRM).
Median age was 58 years (interquartile range IQR, 53-63). Dynamic international prognostic scoring system-plus was intermediate (n = 28) or high (n = 18). Donors were related (n = 19) or unrelated (n = 27). Cumulative incidence of NRM was 9.7% (95% confidence interval CI, 0-20.3) at day 100 and at 3 years in the high-dose group and 0% in the low-dose group at day 100, which increased to 20% (95% CI, 0-41.9) at 3 years. With a median follow-up of 5.1 years (IQR, 3.8-6), 3-year relapse was 32.3% (95% CI, 15.4-49.1) in high dose versus 53.3% (95% CI, 26.6-80.1) in low dose. Event-free survival was 58% (95% CI, 43-78) versus 27% (95% CI, 12-62), and overall survival was 74% (95% CI, 60-91) versus 60% (95% CI, 40-91). In multivariate analysis, high-dose busulfan had a trend toward lower relapse (hazard ratio, .44; 95% CI, .18-1.07; P = .07), with no impact on NRM.
Intensifying the Bu-Flu regimen using pharmacokinetic-monitoring appears to be promising in reducing relapse without increasing NRM.
We are in the midst of a pandemic with the COVID-19 virus, a pathogen with potential severe manifestations. A major clinical question is whether it is safe to undergo hematopoietic stem cell ...transplantation (HSCT) shortly after COVID-19 infection. A total of 21 patients received HSCT following a diagnosis of COVID-19 infection at our institution between 7/30/2020 and 4/14/2021. The majority (n=13, 62%) received an allogeneic (ALLO) HSCT from an HLA-matched related (n=5), -matched unrelated (n=6), or haploidentical (n=2) donor. The remaining 8 patients received autologous (AUTO) HSCT. Among ALLO-HSCT recipients, 4 (31%), 5 (38%), 3 (23%), and 1 (8%) patients had grade 1, 2, 3, and 4, manifestations respectively, scored according to the WHO COVID-19 infection severity grading system. Among AUTO-HSCT recipients, 5 (62%), 1 (12%), and 2 (25%) patients had grade 0, 1, and 2 manifestations, respectively. All patients had resolution of COVID-19 symptoms before HSCT. In recipients of ALLO-SCT, the median time from diagnosis of the COVID infection to HSCT was 134 (range: 55-311) days. Median age of recipients was 53 (range: 17-71) years and the majority (69%) of patients were male. Only one patient was <18 years old, and 38% were >60 years. Patients received ALLO-HSCT for treatment of acute myeloid leukemia or myelodysplastic syndrome (n=7, 54%), acute lymphoblastic leukemia (n=2, 15%), chronic lymphoblastic leukemia (n=2, 15%), and Hodgkin's (n=1, 8%) or non-Hodgkin's lymphoma (n=1, 15%). Most (62%) patients were not in remission at the time of HSCT. The median hematopoietic cell transplant-co-morbidity index (HCT-CI) score was 3 (range 0-6); one patient had a history of diabetes and another of hypertension before HSCT. Conditioning regimen was myeloablative in 61%, and stem cell source was peripheral blood (PB) in 92% of transplants. Median time to neutrophils engraftment was 15 (range: 10-20) days. With a median follow-up of 3.5 (range: 0.4-8) months since ALLO-HSCT, two patients died and another two experienced progression of the underlying malignancy. Three patients were diagnosed with grade 2 and none with grade 3 or 4 acute graft-versus-host disease (GvHD). The deaths occurred among patients with COVID-19 infection grade 2 and 3. The primary cause of death was attributed to alveolar hemorrhage/pneumonitis (no organism identified) and acute GvHD, respectively. Overall survival was 89% (95% confidence interval CI:43-98) and 76% (95% CI 33-93) at 3 and 6 months, respectively. In recipients of AUTO-HSCT, the median time from diagnosis of the COVID-19 infection to HSCT was 55 (range: 20-157) days. Median age of recipients was 55 (range: 34-75) years, and the majority (62%) of patients were male. One (12%) patient was >60 years. Patients received AUTO-HSCT for treatment of Hodgkin's (n=1, 15%) or non-Hodgkin's (n=4, 50%) lymphoma, or multiple myeloma (n=3, 37%). Six (75%) patients were in remission at the time of HSCT. The median HCT-CI score was 2 (range 0-6). None of the patients had a history of diabetes or hypertension before transplant. Conditioning regimen was myeloablative and stem cell source was PB for all patients. Median time to neutrophils engraftment was 10 (range: 9-13) days. With a median follow-up of 4 (range: 0.8-9) months since AUTO-HSCT, one patient with grade 1 COVID infection died as a result of a candida/cytomegalovirus infection, and none of the patients experienced progression of the underlying malignancy. Overall survival was 100% and 75% (95% CI 13-96) at 3 and 6 months respectively. After HSCT, one ALLO and two AUTO asymptomatic patients had a positive nasal swab COVID-19 PCR assay possibly due to delayed shedding of the virus. None of the 21 patients developed active COVID infections post-transplant. In conclusion, allogeneic and autologous hematopoietic transplantation can be performed in patients after COVID-19 infection. Two of 13 allogeneic and one of 8 autologous recipients experienced non-relapse mortality, none directly related to COVID-19 infection. Patients recovering from COVID-19 infection should be considered eligible for hematopoietic transplantation as clinically indicated.
Shpall: Magenta: Honoraria; Affimed: Patents & Royalties; Novartis: Honoraria; Navan: Consultancy; Magenta: Consultancy; Axio: Consultancy; Adaptimmune: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Novartis: Consultancy; Takeda: Patents & Royalties. Chemaly: Other: Other: Compensation: I am a consultant and advisor on companies who are developing new agents such as Merck, Ansun, and Janssen.
Background: Allogeneic stem-cell transplantation (alloSCT) remains the only curative treatment for patients with advanced AML. However, only a minority of these patients achieve disease control prior ...to transplantation. Natural Killer (NK) cells have potent anti-leukemic activity but are functionally deficient in AML. Adoptive NK-cell therapy using high-doses of functionally active NK-cells could overcome these limitations. We previously developed an ex vivo NK-cell expansion method based on K562 feeder cells modified to express membrane bound IL-21 (mbIL-21) and 4-1BB ligand, (FC21), which resulted in high numbers of hyperfunctional FC21-NK cells with enhanced cytotoxicity and cytokine production. Here we report outcomes of a phase I clinical trial designed to assess the safety, feasibility and maximum tolerated dose (MTD) of haploidentical FC21-NK cells for patients with relapse/refractory (R/R) AML at MD Anderson Cancer Center.
Methods: Eligible patients were ≥18 years, KPS ≥70 with good organ function. Patients with relapsed AML after alloSCT were eligible if they had no active GVHD and did not require immunosuppression. Haploidentical donors were selected based on KIR characteristics, when multiple donors were available. Donor NK cells were expanded over 3 weeks and cryopreserved. Three dose levels between 106-108 cells/kg were planned. Patients received cytoreductive chemotherapy with fludarabine 30 mg/m2/day and cytarabine 2 g/m2/day for 5 days (4 days for age >60) and G-CSF (subsequently eliminated). 3-7 days after chemotherapy, patients received FC21-NK cell infusions 3 times per week, up to 6 infusions.
Results: As of 4/14/2020, 15 patients were screened, 12 of whom were eligible and received the FC21-NK cells. Median age was 60 years (range 25-70); 6 (50%) had adverse cytogenetics, 8 (66.7%) had adverse ELN genetic risk, 6 (50%) had primary induction failure, 2 (16.7%) had CNS disease and 4 (33.3%) had secondary AML. Median number of prior treatment regimens was 5 (range 2-8), median blast count at enrollment was 47% (range 7-88).
Median time from diagnosis to enrollment and to first NK-cell infusion was 16.6 (range 2.5-98.1) and 17.2 (range 3.1-98.6) months, respectively. Donor-recipient NK-cell alloreactivity was seen in 5 patients (41.7%). Median number of NK-cell infusion was 6 (range 3-6); 8 (66.7%) and 4 (33.3%) patients received NK-cell dose of 1 X106 and 1 X107 cells/kg, respectively. MTD was not reached. Seven patients had ANC recovery post-NK cell infusion with cumulative incidence (CI) of ANC recovery to 500/mm3 at 60 days of 58.3%. Eight patients (66.7%) achieved complete remission (CR) (N=4, 33.3%) or CR with incomplete hematologic recovery (CRi) (N=4, 33.3%) at 30 days post-NK cell infusion. One patient with CR had negative minimal residual disease (MRD). Five patients (41.7%) proceeded to haploidentical alloSCT from the same donor and were transplanted in CR/CRi, all but one with persistent MRD.
With a median follow-up of 13 months (range 4.1-42.7), median OS and DFS were 17.6 and 3.3 months, and 28 and 20 months for patients receiving alloSCT, respectively. Other outcomes including 2-year OS, DFS, relapse and TRM are shown in Figure 1 and Table 1. No infusion related toxicity or cytokine release syndrome was observed. Two patients were evaluable for FC21-NK cell persistence with haplotype-specific anti-HLA antibodies. FC21-NK cells were detected 5 and 6 weeks after the last FC21-NK cell infusion, respectively. A progressive decrease of the blast population with progressive expansion of the FC21-NK cell population after repeated NK-cell infusions was noted in samples collected from one pt (Figure 2). Persistence is also being evaluated by STR chimerism.
Conclusions: Multiple infusions of FC21-NK cells yielded unprecedented outcomes with 66.7% of patients responding and approximately half proceeding to alloSCT in a heavily pre-treated, ultra-refractory, high-risk patient population. Responses were observed irrespective of dose. FC21-NK cell therapy was very well tolerated with no attributable AEs and were shown to persist for at least 5 weeks after infusion. These encouraging results warrant further clinical evaluation of FC21-NK cells in R/R AML patients.
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Ciurea:Kiadis Pharma: Current equity holder in publicly-traded company, Research Funding. Schafer:Kiadis Pharma: Current Employment. Shpall:Zelluna: Membership on an entity’s Board of Directors or advisory committees; Adaptimmune: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Magenta: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; Takeda: Other: Licensing Agreement. Konopleva:Calithera: Research Funding; Eli Lilly: Research Funding; Kisoji: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Forty-Seven: Consultancy, Research Funding; Sanofi: Research Funding; AstraZeneca: Research Funding; Agios: Research Funding; Ablynx: Research Funding; AbbVie: Consultancy, Research Funding; Ascentage: Research Funding; Rafael Pharmaceutical: Research Funding; Cellectis: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Stemline Therapeutics: Consultancy, Research Funding. Lee:Kiadis Pharma Netherlands B.V: Consultancy, Current equity holder in publicly-traded company, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Champlin:Actinium: Consultancy; Johnson and Johnson: Consultancy; Omeros: Consultancy; DKMS America: Membership on an entity’s Board of Directors or advisory committees; Cytonus: Consultancy; Genzyme: Speakers Bureau; Takeda: Patents & Royalties.
Delayed engraftment is a major limitation of cord blood transplantation (CBT), due in part to a defect in the cord blood (CB) cells’ ability to home to the bone marrow. Because this defect appears ...related to low levels of fucosylation of cell surface molecules that are responsible for binding to P- and E-selectins constitutively expressed by the marrow microvasculature, and thus for marrow homing, we conducted a first-in-humans clinical trial to correct this deficiency. Patients with high-risk hematologic malignancies received myeloablative therapy followed by transplantation with 2 CB units, one of which was treated ex vivo for 30 minutes with the enzyme fucosyltransferase-VI and guanosine diphosphate fucose to enhance the interaction of CD34+ stem and early progenitor cells with microvessels. The results of enforced fucosylation for 22 patients enrolled in the trial were then compared with those for 31 historical controls who had undergone double unmanipulated CBT. The median time to neutrophil engraftment was 17 days (range, 12-34 days) compared with 26 days (range, 11-48 days) for controls (P = .0023). Platelet engraftment was also improved: median was 35 days (range, 18-100 days) compared with 45 days (range, 27-120 days) for controls (P = .0520). These findings support ex vivo fucosylation of multipotent CD34+ CB cells as a clinically feasible means to improve engraftment efficiency in the double CBT setting. The trial is registered to www.clinicaltrials.gov as #NCT01471067.
•Ex vivo fucosylation of cord blood cells improves their homing capacities, leading to faster neutrophil and platelet engraftments.•This method is quick, safe, and does not require a GMP laboratory; therefore, it can be used widely.
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