Clinical use of umbilical cord blood (UCB) for novel indications in regenerative therapy continue... more Clinical use of umbilical cord blood (UCB) for novel indications in regenerative therapy continues to rise, however, whether new indications are proven is less clear. An updated systematic search of the literature, focusing only on controlled clinical studies, is needed to properly assess potential efficacy. After updating our systematic search to April 1, 2018 (PROSPERO protocol CRD42016040157), a total of 16 studies were identified that addressed the treatment of cerebral palsy (four studies), type 1 diabetes (three studies), and nine other novel potential indications where only a single controlled study was identified. In the four controlled studies of patients with cerebral palsy, three used allogeneic cells and reported greater improvement in motor-related scores at 1, 3 and 6 months compared with controls. The results were mixed for other scores at other time points, including additional measures of mental and motor function. One study of autologous UCB treatment reported an improvement in motor function scores at 12 months compared with controls. In the three controlled studies of type 1 diabetes, two studies used autologous cells whereas one used allogeneic cord blood cells to "educate" autologous lymphocytes. Taken together, there was no clear difference in HbA1c levels or daily insulin requirements between treated patients and controls. For the nine published reports with a single controlled study, eight used allogeneic UCB cells and seven infused mesenchymal stromal cells derived from UCB. All but one study reported benefit. Many other published reports that lack a control group were not included in our analysis. More controlled studies are needed that use similar approaches regarding cell source and outcome measures at similar time points. Pooled estimates of results from multiple studies will be essential as published studies remain modest in size. Patients should continue to be enrolled in clinical trials because there are no novel potential indications remain unproven.
Transfusion medicine (Oxford, England), Jan 30, 2018
A scoping review of randomised controlled trials (RCTs) addressing source of cells and choice of ... more A scoping review of randomised controlled trials (RCTs) addressing source of cells and choice of donor for allogeneic haematopoietic cell transplantation (HCT) was performed to create a network of best evidence that allows us to identify new potential indirect comparisons for the strategic development of future studies that connect to the existing evidence network. A total of 19 eligible RCTs (2589 total patients) were identified. Nine studies (1566 patients) compared clinical outcomes following the use of peripheral blood progenitor cells (PBPCs) with bone marrow (BM) from matched related donors (eight studies) or matched unrelated donors (one study). The remaining studies compared BM or PBPCs with various methods of BM stimulation or manipulation (six studies), compared different methods of surface molecule-based selection and/or depletion of grafts (two studies) or compared the optimal number of units for paediatric cord blood transplantation (two studies). No published RCTs comp...
The frequency of cryopreserving blood stem or progenitor products from unrelated donors is not kn... more The frequency of cryopreserving blood stem or progenitor products from unrelated donors is not known and the underlying reasons are poorly documented. Greater insight is needed to develop policies on cryopreservation that balance donor safety with patient needs. Cryopreservation requests between January 1, 2014, and May 31, 2016, at the OneMatch Stem Cell and Marrow Network at Canadian Blood Services were reviewed and a systematic review of the literature was performed. Thirty products of 719 (4.2%) unrelated donor collections facilitated by OneMatch were cryopreserved. Patient-related reasons were most common and included the need to delay transplant for continued antimicrobial treatment (six patients), patient too deconditioned to proceed with scheduled transplant (five patients), and/or need for more treatment for relapsed disease (three patients). Donor-related issues leading to cryopreservation requests were less common (five cases), mainly due to lack of donor availability aft...
Cell-based therapy using umbilical cord blood (UCB) is being used increasingly in novel applicati... more Cell-based therapy using umbilical cord blood (UCB) is being used increasingly in novel applications. To balance heightened public expectations and ensure appropriateness of emerging cell-based treatment choices, regular evidence-based assessment of novel UCB-derived therapies is needed. We performed a systematic search of the literature and identified 57 studies (814 patients) for analysis. Sixteen of these studies (353 patients) included a control group for comparison. The most commonly reported novel indication for therapy was neurologic diseases (25 studies, 476 patients), including studies of cerebral palsy (12 studies, 276 patients). Other indications included diabetes mellitus (9 studies, 149 patients), cardiac and vascular diseases (7 studies, 24 patients), and hepatic diseases (4 studies, 106 patients). Most studies administered total nucleated cells, mononuclear cells, or CD34-selected cells (31 studies, 513 patients), whereas 20 studies described the use of UCB-derived mesenchymal stromal cells. The majority of reports (46 studies, 627 patients) described cellular products obtained from allogeneic sources, whereas 11 studies (187 patients) used autologous products. We identified 3 indications where multiple prospective controlled studies have been published: 4 of 4 studies reported clinical benefit in cerebral palsy, 1 of 3 studies reported benefit for cirrhosis, and 1 of 3 studies reported biochemical response in type 1 diabetes), although heterogeneity among the studies precluded meaningful pooled analysis of results. We anticipate a more clear understanding of the clinical benefit for specific indications once more controlled studies are reported. Patients should continue to be enrolled on registered clinical trials for novel therapies. Blood establishments, transplantation centers, and regulatory bodies need to prepare for greater clinical demand.
Effective treatments are lacking for the treatment of steroid-refractory graft-versus-host diseas... more Effective treatments are lacking for the treatment of steroid-refractory graft-versus-host disease (GVHD), a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Mesenchymal stromal cells (MSCs) have demonstrated promise but there is uncertainty regarding their clinical effectiveness. A systematic scoping review of the literature was performed to characterize the heterogeneity of published studies and identify opportunities for standardization. Thirty studies were identified, including 19 studies (507 patients) addressing the treatment of acute or chronic GVHD and 11 prevention studies (277 patients). Significant heterogeneity was observed in the age and diagnoses of study subjects, intensity and specifics of the conditioning regimens, degree of HLA matching, and source of hematopoietic cells. MSCs were derived from bone marrow (83% of studies), cord blood (13%), or adipose tissue (3%) and were cryopreserved from third-party allogeneic donors in the majority of studies (91% of prevention studies and 63% of treatment studies). Culture conditions and media supplements were highly variable and characterization of MSCs did not conform to all International Society for Cellular Therapy criteria in any study. MSCs were harvested from cell culture at passage 1 to 7 and the dosage of MSCs ranged from 0.3 to 10 Â 10 6 /kg, using varying schedules of administration. Treatment response criteria were not standardized and effectiveness in controlled treatment studies (5 studies) was unconvincing. Details of actively recruiting trials suggest heterogeneity still persists with only 53% of registered trials describing the use of standard GVHD response criteria and few detailing methods of MSC manufacturing. Future studies will need to make substantial coordinated efforts to reduce study heterogeneity and clarify the role of MSCs in GVHD.
Clinical use of umbilical cord blood (UCB) for novel indications in regenerative therapy continue... more Clinical use of umbilical cord blood (UCB) for novel indications in regenerative therapy continues to rise, however, whether new indications are proven is less clear. An updated systematic search of the literature, focusing only on controlled clinical studies, is needed to properly assess potential efficacy. After updating our systematic search to April 1, 2018 (PROSPERO protocol CRD42016040157), a total of 16 studies were identified that addressed the treatment of cerebral palsy (four studies), type 1 diabetes (three studies), and nine other novel potential indications where only a single controlled study was identified. In the four controlled studies of patients with cerebral palsy, three used allogeneic cells and reported greater improvement in motor-related scores at 1, 3 and 6 months compared with controls. The results were mixed for other scores at other time points, including additional measures of mental and motor function. One study of autologous UCB treatment reported an improvement in motor function scores at 12 months compared with controls. In the three controlled studies of type 1 diabetes, two studies used autologous cells whereas one used allogeneic cord blood cells to "educate" autologous lymphocytes. Taken together, there was no clear difference in HbA1c levels or daily insulin requirements between treated patients and controls. For the nine published reports with a single controlled study, eight used allogeneic UCB cells and seven infused mesenchymal stromal cells derived from UCB. All but one study reported benefit. Many other published reports that lack a control group were not included in our analysis. More controlled studies are needed that use similar approaches regarding cell source and outcome measures at similar time points. Pooled estimates of results from multiple studies will be essential as published studies remain modest in size. Patients should continue to be enrolled in clinical trials because there are no novel potential indications remain unproven.
Transfusion medicine (Oxford, England), Jan 30, 2018
A scoping review of randomised controlled trials (RCTs) addressing source of cells and choice of ... more A scoping review of randomised controlled trials (RCTs) addressing source of cells and choice of donor for allogeneic haematopoietic cell transplantation (HCT) was performed to create a network of best evidence that allows us to identify new potential indirect comparisons for the strategic development of future studies that connect to the existing evidence network. A total of 19 eligible RCTs (2589 total patients) were identified. Nine studies (1566 patients) compared clinical outcomes following the use of peripheral blood progenitor cells (PBPCs) with bone marrow (BM) from matched related donors (eight studies) or matched unrelated donors (one study). The remaining studies compared BM or PBPCs with various methods of BM stimulation or manipulation (six studies), compared different methods of surface molecule-based selection and/or depletion of grafts (two studies) or compared the optimal number of units for paediatric cord blood transplantation (two studies). No published RCTs comp...
The frequency of cryopreserving blood stem or progenitor products from unrelated donors is not kn... more The frequency of cryopreserving blood stem or progenitor products from unrelated donors is not known and the underlying reasons are poorly documented. Greater insight is needed to develop policies on cryopreservation that balance donor safety with patient needs. Cryopreservation requests between January 1, 2014, and May 31, 2016, at the OneMatch Stem Cell and Marrow Network at Canadian Blood Services were reviewed and a systematic review of the literature was performed. Thirty products of 719 (4.2%) unrelated donor collections facilitated by OneMatch were cryopreserved. Patient-related reasons were most common and included the need to delay transplant for continued antimicrobial treatment (six patients), patient too deconditioned to proceed with scheduled transplant (five patients), and/or need for more treatment for relapsed disease (three patients). Donor-related issues leading to cryopreservation requests were less common (five cases), mainly due to lack of donor availability aft...
Cell-based therapy using umbilical cord blood (UCB) is being used increasingly in novel applicati... more Cell-based therapy using umbilical cord blood (UCB) is being used increasingly in novel applications. To balance heightened public expectations and ensure appropriateness of emerging cell-based treatment choices, regular evidence-based assessment of novel UCB-derived therapies is needed. We performed a systematic search of the literature and identified 57 studies (814 patients) for analysis. Sixteen of these studies (353 patients) included a control group for comparison. The most commonly reported novel indication for therapy was neurologic diseases (25 studies, 476 patients), including studies of cerebral palsy (12 studies, 276 patients). Other indications included diabetes mellitus (9 studies, 149 patients), cardiac and vascular diseases (7 studies, 24 patients), and hepatic diseases (4 studies, 106 patients). Most studies administered total nucleated cells, mononuclear cells, or CD34-selected cells (31 studies, 513 patients), whereas 20 studies described the use of UCB-derived mesenchymal stromal cells. The majority of reports (46 studies, 627 patients) described cellular products obtained from allogeneic sources, whereas 11 studies (187 patients) used autologous products. We identified 3 indications where multiple prospective controlled studies have been published: 4 of 4 studies reported clinical benefit in cerebral palsy, 1 of 3 studies reported benefit for cirrhosis, and 1 of 3 studies reported biochemical response in type 1 diabetes), although heterogeneity among the studies precluded meaningful pooled analysis of results. We anticipate a more clear understanding of the clinical benefit for specific indications once more controlled studies are reported. Patients should continue to be enrolled on registered clinical trials for novel therapies. Blood establishments, transplantation centers, and regulatory bodies need to prepare for greater clinical demand.
Effective treatments are lacking for the treatment of steroid-refractory graft-versus-host diseas... more Effective treatments are lacking for the treatment of steroid-refractory graft-versus-host disease (GVHD), a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Mesenchymal stromal cells (MSCs) have demonstrated promise but there is uncertainty regarding their clinical effectiveness. A systematic scoping review of the literature was performed to characterize the heterogeneity of published studies and identify opportunities for standardization. Thirty studies were identified, including 19 studies (507 patients) addressing the treatment of acute or chronic GVHD and 11 prevention studies (277 patients). Significant heterogeneity was observed in the age and diagnoses of study subjects, intensity and specifics of the conditioning regimens, degree of HLA matching, and source of hematopoietic cells. MSCs were derived from bone marrow (83% of studies), cord blood (13%), or adipose tissue (3%) and were cryopreserved from third-party allogeneic donors in the majority of studies (91% of prevention studies and 63% of treatment studies). Culture conditions and media supplements were highly variable and characterization of MSCs did not conform to all International Society for Cellular Therapy criteria in any study. MSCs were harvested from cell culture at passage 1 to 7 and the dosage of MSCs ranged from 0.3 to 10 Â 10 6 /kg, using varying schedules of administration. Treatment response criteria were not standardized and effectiveness in controlled treatment studies (5 studies) was unconvincing. Details of actively recruiting trials suggest heterogeneity still persists with only 53% of registered trials describing the use of standard GVHD response criteria and few detailing methods of MSC manufacturing. Future studies will need to make substantial coordinated efforts to reduce study heterogeneity and clarify the role of MSCs in GVHD.
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