-
1.
Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy
Lauer, A., Speroni, S. L., Choi, M., Da, X., Duncan, C., McCarthy, S., Krishnan, V., Lusk, C. A., Rohde, D., Hansen, M. B., et al
Nature communications. 2023;14(1):1900
Abstract
Blood-brain barrier disruption marks the onset of cerebral adrenoleukodystrophy (CALD), a devastating cerebral demyelinating disease caused by loss of ABCD1 gene function. The underlying mechanism are not well understood, but evidence suggests that microvascular dysfunction is involved. We analyzed cerebral perfusion imaging in boys with CALD treated with autologous hematopoietic stem-cells transduced with the Lenti-D lentiviral vector that contains ABCD1 cDNA as part of a single group, open-label phase 2-3 safety and efficacy study (NCT01896102) and patients treated with allogeneic hematopoietic stem cell transplantation. We found widespread and sustained normalization of white matter permeability and microvascular flow. We demonstrate that ABCD1 functional bone marrow-derived cells can engraft in the cerebral vascular and perivascular space. Inverse correlation between gene dosage and lesion growth suggests that corrected cells contribute long-term to remodeling of brain microvascular function. Further studies are needed to explore the longevity of these effects.
-
2.
Side Effects After Use of Bedside Thaw Method for Umbilical Cord Blood Stem Cell Allogeneic Transplantations in a Pediatric Cohort: A Single-center Experience
Builes, N., Niño-Serna, L., Combariza, J. F.
Hematology/oncology and stem cell therapy. 2023;17(1):51-59
Abstract
BACKGROUND AND OBJECTIVES Several strategies and procedures have been described for thawing umbilical cord blood (UCB) products. The ideal method for each center depends on the resources, staff training, and access to each of these. We retrospectively evaluated the incidence of side effects using the bedside thaw method after unrelated UCB transplantation. PATIENTS AND METHODS For 34 children, patient, donor, graft characteristics, and side effects were identified. In addition, we attempted to identify the risk factors that could be associated with side effects. RESULTS 68% of patients experienced any adverse reaction. All the reactions were mild and transient events. The most frequent side effects were vomiting, hypertension, hemolytic reactions, and fever. There were more gastrointestinal events with a faster infusion rate. CONCLUSION The thawed at the bedside method is a practical, easy, and safe technique for cord blood transplantation in pediatric-patient settings.
-
3.
T-cell replete cord transplants give superior outcomes in high-risk and relapsed/refractory pediatric myeloid malignancy
Horgan, C., Mullanfiroze, K., Rauthan, A., Patrick, K., Butt, N. A., Mirci-Danicar, O., O'Connor, O., Furness, C., Deshpande, A., Lawson, S., et al
Blood advances. 2023;7(10):2155-2165
-
-
-
Free full text
-
Full text
-
Editor's Choice
Abstract
Stem cell transplant (SCT) outcomes in high-risk and relapsed/refractory (R/R) pediatric acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been historically poor. Cord blood (CB) allows T-cell replete CB transplant (TRCB), enabling enhanced graft-versus-leukemia. We consecutively collected data from 367 patients undergoing TRCB (112 patients) or other cell source (255 patients) SCT for pediatric AML/MDS in the United Kingdom and Ireland between January 2014 and December 2021. Data were collected about the patient's demographics, disease, and its treatment; including previous transplant, measurable residual disease (MRD) status at transplant, human leukocyte antigen-match, relapse, death, graft versus host disease (GvHD), and transplant-related mortality (TRM). Univariable and multivariable analyses were undertaken. There was a higher incidence of poor prognosis features in the TRCB cohort: 51.4% patients were MRD positive at transplant, 46.4% had refractory disease, and 21.4% had relapsed after a previous SCT, compared with 26.1%, 8.6%, and 5.1%, respectively, in the comparator group. Event free survival was 64.1% within the TRCB cohort, 50% in MRD-positive patients, and 79% in MRD-negative patients. To allow for the imbalance in baseline characteristics, a multivariable analysis was performed where the TRCB cohort had significantly improved event free survival, time to relapse, and reduced chronic GvHD, with some evidence of improved overall survival. The effect appeared similar regardless of the MRD status. CB transplant without serotherapy may be the optimal transplant option for children with myeloid malignancy.
PICO Summary
Population
Children with AML/MDS and receiving transplant in UK centres between 2014 and 2021 (n=367)
Intervention
T-cell replete cord blood transplant (TRCB cohort, n=112)
Comparison
Transplant from any other cell source (n=255)
Outcome
Event free survival was 64.1% within the TRCB cohort, 50% in MRD-positive patients, and 79% in MRD-negative patients. To allow for the imbalance in baseline characteristics, a multivariable analysis was performed where the TRCB cohort had significantly improved event free survival, time to relapse, and reduced chronic GvHD, with some evidence of improved overall survival. The effect appeared similar regardless of the MRD status.
-
4.
TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis
Merli, P., Algeri, M., Galaverna, F., Bertaina, V., Lucarelli, B., Boccieri, E., Becilli, M., Quagliarella, F., Rosignoli, C., Biagini, S., et al
Blood. 2023
Abstract
TCRαβ/CD19-cell depletion is a promising graft manipulation technique frequently used in the context of HLA-haploidentical hematopoietic stem cell transplantation (HSCT). We previously reported the results of a phase I-II clinical trial (NCT01810120) to assess the safety and the efficacy of this type of ex-vivo T cell-depletion in 80 children with acute leukemia, showing promising survival outcomes. We now report an updated analysis on a cohort of 213 children with a longer follow-up (median value of 47.6 months for surviving patients). With a 5-year cumulative incidence of non-relapse mortality of 5.2% (95% confidence interval, CI, 2.8-8.8) and a cumulative incidence of relapse of 22.7% (95% CI, 16.9-29.2), projected 10-year overall and disease-free survival (DFS) were 75.4% (95% CI 68.6-80.9) and 71.6% (95% CI 64.4-77.6), respectively. Cumulative incidence of both grade II-IV acute and chronic GvHD were low (14.7% and 8.1%, respectively). In a multivariable analysis for DFS including also type of disease, use of total body irradiation in the conditioning regimen [hazard ratio (HR) 0.5 (95% CI, 0.26-0.98, p=0.04)], disease status at HSCT [CR>3 versus CR1/2; HR 2.23 (95% CI, 1.20-4.16, p=0.01] and high levels of pre-HSCT minimal residual disease [HR 2.09 (95% CI, 1.01-4.33, p=0.04)] were independently associated with outcome. In summary, besides confirming the good outcome results already reported (which are almost superimposable to those of transplant from HLA-matched donors), this clinical update allows the identification of patients at higher risk of treatment failure for whom personalized approaches, aimed at reducing the risk of relapse, are warranted.
-
5.
Immunological recovery following HLA-matched CD3+ TCR αß+/CD19+ depleted hematopoietic stem cell transplantation in children
Sperl, D., Lang, P., Benesch, M., Bainschab, A., Urban, C., Wilfing, R., Feuchtinger, T., Döring, M., Seitz, C., Strenger, V., et al
Pediatric transplantation. 2022;:e14285
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for children with both malignant and nonmalignant diseases. T-cell depletion techniques may result in reduced transplant-related mortality compared with unmanipulated grafts due to a lower incidence of GvHD. METHODS Immune recovery and outcome were analyzed in a cohort of 23 patients with malignant and nonmalignant diseases who received CD3+TCRαβ+ T- and B-cell-depleted allografts from matched donors after reduced-intensity or myeloablative conditioning. The median number of CD34+, CD3+TCRαβ+, and CD19+B-cells infused was 12.7 × 10(6) /kg, 16.8 × 10(3) /kg, and 96 × 10(3) /kg bodyweight. RESULTS With a median follow-up of 36 (range 1-73) months, overall survival and disease-free survival at 3 years were 65.2% and 60.8%. Eight patients died, six due to the underlying disease and two of extended visceral cGvHD. Immune reconstitution, disease-free, and overall survivals were similar compared with a historical cohort of 23 patients transplanted with matched unmanipulated bone marrow. A significant lower rate of higher grade (III-IV) aGvHD was observed in the manipulated HSCT group (8.7% vs. 26%; p = 0.001), whereas the incidence of cGvHD was equal. CONCLUSIONS Our data suggest that this graft manipulation strategy could be a safe and effective alternative to conventional HSCT techniques in matched donors.
-
6.
NK cell content does not seem to influence engraftment in ex vivo T cell depleted haploidentical stem cell transplantation
Merli, P., Eichholz, T., Catanoso, M. L., Lang, P., Locatelli, F.
Stem cell reports. 2022;17(3):443-445
-
7.
Alpha-beta T and B-cell depleted HLA-haploidentical HSCT in children with myelodysplastic syndromes
Merli, P., Pagliara, D., Mina, T., Bertaina, V., Li Pira, G., Lazzaro, S., Biagini, S., Galaverna, F., Strocchio, L., Carta, R., et al
Haematologica. 2022
Abstract
Not available.
-
8.
T-Cell Depleted Haploidentical Transplantation in Children With Hematological Malignancies: A Comparison Between CD3+/CD19+ and TCRαβ+/CD19+ Depletion Platforms
Gonzalez-Vicent, M., Molina, B., Lopez, I., Zubicaray, J., Ruiz, J., Vicario, J. L., Sebastián, E., Iriondo, J., Castillo, A., Abad, L., et al
Frontiers in oncology. 2022;12:884397
Abstract
BACKGROUND T-cell depleted (TCD) haploidentical transplantation using CD3+/CD19+ and TCRαβ+/CD19+ depletion techniques has been increasingly used in children with hematological malignancies. We present a retrospective study aimed to compare transplant outcomes in children with leukemia receiving a TCD haploidentical transplant using either CD3+/CD19+ or TCRαβ+/CD19+ platforms. METHODS A total of 159 children with leukemia (ALL=80) (AML=79) that received a TCD haploidentical transplantation using either CD3+/CD19+ (n=79) or TCRαβ+/CD19+ (n=80) platforms between 2005 and 2020 were included. Median age was 9 years in both groups. There were no differences in patient, donor, and transplant characteristics between groups except for donor KIR B genotype more frequent in the TCRαβ+/CD19+ group (91%) than in the CD3+/CD19+ group (76%) (p=0.009) and a high number of NK+ cells and lower CD19+ cells infused in the TCRαβ+/CD19+ group (35.32x10(6)/kg and 0.06 x10(6)/Kg) than in the CD3+/CD19 group (24.6x10(6)/Kg and 0.25 x10(6)/Kg) (p=0.04 and p=0.0001), respectively. Conditioning was based on TBF. Median follow-up for survivors was 11 years (range; 8-16 y) in CD3+/CD19+ group and 5 years (range; 2-9 y) in the TCRαβ+/CD19+ group. RESULTS Engraftment kinetics were similar in both groups (13 days for neutrophils and 10 days for platelets). There was no difference in the incidence of acute GvHD II-IV (29 ± 5% in the CD3+/CD19+ group vs 38 ± 5% in the TCRαβ+/CD19+ group) and chronic GvHD (32 ± 5% vs 23 ± 4%, respectively). NRM was 23 ± 5% in the CD3+/CD19+group vs 21 ± 4% in the TCRαβ+/CD19+group. Relapse incidence was also similar, 32 ± 5% vs 34 ± 6%, respectively. DFS and OS were not different (45 ± 5% vs 45 ± 6% and 53 ± 6% vs 58 ± 6% respectively). As there were no differences on transplant outcomes between groups, we further analyzed all patients together for risk factors associated with transplant outcomes. On multivariate analysis, we identified that early disease status at transplant (HR: 0.16; 95%CI (0.07-0.35) (p=0.0001), presence of cGvHD (HR: 0.38; 95%CI (0.20-0.70) (p= 0.002), and donor KIR-B genotype (HR: 0.50; 95%CI (0.32-0.90) (p=0.04) were associated with better DFS. CONCLUSIONS Our data suggest that there are no advantages in transplant outcomes between TCD platforms. Risk factors for survival are dependent on disease characteristic, donor KIR genotype, and chronic GvHD rather than the TCD platform used.
-
9.
Lymphoid and myeloid immune cell reconstitution after nicotinamide-expanded cord blood transplantation
de Koning, C., Tao, W., Lacna, A., van Veghel, K., Horwitz, M. E., Sanz, G., Jagasia, M. H., Wagner, J. E., Stiff, P. J., Hanna, R., et al
Bone marrow transplantation. 2021
Abstract
Omidubicel (nicotinamide-expanded cord blood) is a potential alternative source for allogeneic hematopoietic cell transplantation (HCT) when an HLA-identical donor is lacking. A phase I/II trial with standalone omidubicel HCT showed rapid and robust neutrophil and platelet engraftment. In this study, we evaluated the immune reconstitution (IR) of patients receiving omidubicel grafts during the first 6 months post-transplant, as IR is critical for favorable outcomes of the procedure. Data was collected from the omidubicel phase I-II international, multicenter trial. The primary endpoint was the probability of achieving adequate CD4+ T-cell IR (CD4IR:?>?50?×?10(6)/L within 100 days). Secondary endpoints were the recovery of T-cells, natural killer (NK)-cells, B-cells, dendritic cells (DC), and monocytes as determined with multicolor flow cytometry. LOESS-regression curves and cumulative incidence plots were used for data description. Thirty-six omidubicel recipients (median 44; 13-63 years) were included, and IR data was available from 28 recipients. Of these patients, 90% achieved adequate CD4IR. Overall, IR was complete and consisted of T-cell, monocyte, DC, and notably fast NK- and B-cell reconstitution, compared to conventional grafts. Our data show that transplantation of adolescent and adult patients with omidubicel results in full and broad IR, which is comparable with IR after HCT with conventional graft sources.
-
10.
Allogeneic cord blood red blood cells: assessing cord blood unit fractionation and validation
Bianchi, M., Orlando, N., Barbagallo, O., Sparnacci, S., Valentini, C. G., Carducci, B., Teofili, L.
Blood transfusion = Trasfusione del sangue. 2020
Abstract
BACKGROUND For neonates and preterm infants, in whom a transfusion dose is low, the use of red blood cells (RBC) from cord blood appears to be feasible. Standardisation of fractionation and identification and assessment of quality control parameters for such RBC are still lacking. MATERIAL AND METHODS We describe the process used to obtain RBC from cord blood for transfusion purposes, including quality controls to evaluate fractionation performance and the effects of storage. The cord RBC, to which SAG-M was added, were sampled on the day of fractionation, and 7 and 14 days (end of storage) later in order to measure the complete blood count, biochemical parameters and residual white blood cells. We also assessed microbial contamination. RESULTS Data relative to 279 cord blood units were evaluated. The median gestational age at collection was 40 weeks (interquartile range [IQR] 39.1-40.7) and the median volume was 90 mL (IQR 81-103). Units were subjected to automated fractionation with Compomat, and packed RBC were suspended in SAG-M solution. The median volume of the SAG-M-suspended units was 31 mL (IQR 24.0-38.1) and the median haematocrit was 54.2% (IQR 49.4-59.5). The median volume after leucoreduction was 22 mL (IQR 17-28), with the volume decrease being similar in units leucoreduced before (n=75) or after (n=204) storage. The haematocrit of leucoreduced units was higher than that of buffy coat-depleted units. Storage at 2-6 °C for 14 days was accompanied by an increase of potassium levels and percentage of haemolysis. Microbial cultures were positive for 2.9% of the collected units. DISCUSSION Fractionation of whole cord blood can provide RBC concentrates with similar baseline characteristics as units from adults. The transfusion dose and quality of the units appear safe and suitable for clinical use in neonates, with a satisfactory haematocrit and residual white blood cell content, despite a very variable collection volume.