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1.
Validation of a Parvovirus B19 NAT Assay for Screening of Umbilical Cord Blood for Allogenic Hematopoietic Stem Cell Donation
Steininger, P., Korn, K., Hackstein, H., Strasser, E. F.
Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie. 2024;51(1):48-51
Abstract
INTRODUCTION Parvovirus B19 transmitted by umbilical cord blood (UCB) products may cause severe disease in allogenic hematopoietic stem cell transplant recipients. Thus, commercially available nucleic acid test (NAT) assays for highly sensitive detection of parvovirus B19 DNA validated for the specimen cord blood plasma (CBP) are required to avoid parvovirus B19 transmission by umbilical hematopoietic stem cell preparations. METHODS The multiplex cobas DPX NAT assay was validated for detection of parvovirus B19 DNA in CBP derived from citrate anticoagulated UCB units which have been processed by the Rubinstein method. In total, 363 retained CBP samples pretested negative for parvovirus B19 DNA were prepared for analyzing sensitivity, specificity, and interference of that NAT assay. The 3rd WHO International Standard for parvovirus B19 DNA was used for determining the 95% limit of detection (LOD95) by probit analysis. RESULTS The validation of the parvovirus B19 NAT assay for CBP demonstrated high sensitivity, specificity, intra- and inter-assay precision. Dilution series and replicate analyses showed a high linearity of the assay with a coefficient of determination above 0.99 and revealed a LOD95 of 17 International Units (IU)/mL (95% confidence interval, 14-44 IU/mL) for parvovirus B19 DNA in CBP samples. CONCLUSION The validation of a commercially available parvovirus B19 NAT assay for the specimen CBP demonstrated a high assay performance fulfilling German guidelines and international regulations.
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A critical assessment of dose effects of post-thaw CD34 on autologous stem cell transplantation treatment of haematological malignancies
Duarte, G. C., Butler, A., Atkinson, G., Badami, K., Wei, W. H.
EJHaem. 2023;4(2):419-427
Abstract
A consensus threshold of pre-cryopreservation CD34-positive cells (CD34s) has been used as the minimum dose to initiate autologous stem cell transplantation (ASCT). Advances in cryopreservation posed a debate whether post-thaw CD34s might be a superior surrogate instead. We addressed the debate in this retrospective study of 217 adult ASCTs in five different haematological malignancies treated at a single centre. We showed that post-thaw CD34s was highly correlated with pre-cryopreservation CD34s (r = 0.97) and explained ∼2.2% (p = 0.003) of the variation of the post-thaw total nucleated cell viability that however had no power to predict engraftment outcomes. After stratifying the ASCT cases into four dose groups based on post-thaw CD34s reinfused, stepwise multivariate regression analyses detected significant effects in dose group and interactions with diseases for neutrophil and platelet recovery respectively. The significant dose effects and interactions were triggered by two technical outliers in the low dose group, and disappeared in the repeated regressions after exclusion of the outliers where disease and age were the significant predictors remained. Our data clearly support the validity of the consensus threshold in ASCT applications but also highlight neglected conditions where monitoring post-thaw CD34s and clinical attributes are valuable.
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3.
Efficacy of ex vivo purging with CD34+ selection to maximize the effects of autologous stem cell transplantation in peripheral T-cell lymphoma patients
Jeon, Y., Kim, T. Y., Min, G. J., Park, S. S., Park, S., Yoon, J. H., Lee, S. E., Cho, B. S., Eom, K. S., Kim, Y. J., et al
Cytotherapy. 2023
Abstract
BACKGROUND AIMS Peripheral T-cell lymphomas (PTCLs) are rare and aggressive tumors with uncertain optimal treatment. This study investigated the clinical outcomes of high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) after CD34+ selective purging in PTCL patients. METHODS Retrospective analysis included 67 PTCL patients who achieved remission and underwent HDT/ASCT. CD34+ selective purging was performed using CliniMACS® (Miltenyi Biotec, Bergisch Gladbach, Germany). Survival outcomes, engraftment, lymphocyte subsets and viral infections were evaluated. RESULTS CD34+ selective purged autografts were associated with significantly improved overall survival (OS) and disease-free survival (DFS) compared with unpurged autografts (5-year OS, 73.3% versus 37.8%, 5-year DFS, 73.8% versus 33.4%). The cumulative incidence of relapse was also lower in the purged group (31.5% versus 73.3%). Subgroup analysis revealed significant survival benefits in the high-risk group receiving purged autografts. Lymphocyte subset analysis showed increased natural killer (NK) cell counts in the purged group after ASCT. Higher post-ASCT lymphocyte-to-monocyte ratio (LMR) was associated with improved OS and DFS. CONCLUSIONS CD34+ selective purging in PTCL patients undergoing HDT/ASCT improved survival outcomes and reduced relapse risk. The procedure increased NK cell counts and post-ASCT LMR. CD34+ selective purging may minimize autograft tumor cell contamination and enhance efficacy in T-cell lymphomas.
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4.
Improved Outcomes of UM171-Expanded Cord Blood Transplantation Compared with Other Graft Sources: Real-World Evidence
Cohen, S., Bambace, N., Ahmad, I., Roy, J., Tang, X., Zhang, M. J., Burns, L. J., Barabé, F., Bernard, L., Delisle, J. S., et al
Blood advances. 2023
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Editor's Choice
Abstract
Cord blood (CB) transplantation is hampered by low cell dose and high non-relapse mortality (NRM). A phase I-II trial of UM171-expanded CB transplants demonstrated safety and favourable preliminary efficacy. The aim of the current analysis was to retrospectively compare results of the phase I-II trial to those after unmanipulated CB and matched unrelated donor (MUD) transplants. Data from recipients of CB and MUD transplants were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Patients were directly matched for the number of prior allogeneic hematopoietic stem cell transplants (alloHCT), disease and refined Disease Risk Index. Patients were further matched by propensity score for age, comorbidity index and performance status. Primary endpoints included NRM, progression-free survival (PFS), overall survival (OS) and graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) at 1- and 2-years post alloHCT. Overall, 137 CIBMTR (67 CB, 70 MUD) and 22 UM171-expanded CB patients were included. NRM at 1 and 2 years was lower, PFS and GRFS at 2 years and OS at 1 year were improved for UM171-expanded CBs compared to CB controls. Compared to MUD controls, UM171 patients had lower 1- and 2-year NRM, higher 2-year PFS, and higher 1- and 2-year GRFS. Furthermore, UM171-expanded CB recipients experienced less grades III-IV acute GVHD and chronic GVHD compared to MUD graft recipients. Compared to real-world evidence with CB and MUD alloHCT, this study suggests that UM171-expanded CB recipients may benefit from lower NRM and higher GRFS.
PICO Summary
Population
Adults with haematological malignancies enrolled in a clinical trial in USA and Canada, plus matched controls from CIBMTR database (n=159)
Intervention
UM171 cord blood transplant (n=22)
Comparison
Matched controls (n=137) who received cord blood (CB, n=67) or matched unrelated donor transplant (MUD, n=70)
Outcome
Non-relapse mortality (NRM) at 1 and 2 years was lower, progression free survival (PFS) and GvHD-free relapse free survival (GRFS) at 2 years and overall (OS) survival at 1 year were improved for UM171-expanded CBs compared to CB controls. Compared to MUD controls, UM171 patients had lower 1- and 2-year NRM, higher 2-year PFS, and higher 1- and 2-year GRFS. Furthermore, UM171-expanded CB recipients experienced less grades III-IV acute GVHD and chronic GVHD compared to MUD graft recipients.
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Clinical Impact of Cryopreservation of Allogeneic Hematopoietic Cell Grafts During the Onset of the COVID-19 Pandemic
Devine, S. M., Bo-Subait, S., Kuxhausen, M., Spellman, S. R., Bupp, C., Ahn, K. W., Stefanski, H. E., Auletta, J. J., Logan, B. R., Shaw, B. E.
Blood advances. 2023
Abstract
At the onset of the COVID-19 pandemic, the National Marrow Donor Program mandated the cryopreservation of hematopoietic cell grafts from volunteer unrelated donors due to numerous patient and donor safety concerns and logistical hurdles. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) outcomes database, we report the impact of cryopreservation on overall survival (OS) and other outcomes within one year following hematopoietic cell transplantation (HCT). We analyzed 1,543 recipients of cryopreserved allografts receiving HCT at US centers during the first 6-months of the pandemic and compared them to 2,499 recipients of fresh allografts during the same 6-month period in 2019. On multivariable regression analysis, we observed no difference in OS (HR, 1.12; 95% CI: 0.98-1.28; P=0.09), non-relapse mortality (HR, 1.01; 95% CI: 0.84-1.22; P=0.89), graft-versus-host disease (GVHD), or GVHD-free, relapse-free survival (HR 1.03; 95% CI 0.93-1.14; P=0.58) in recipients of cryopreserved versus fresh allografts. Disease-free survival (DFS) was lower in the cryopreserved group (HR, 1.18; 95% CI: 1.05-1.33; P=0.006) due to a higher risk of relapse (HR, 1.21; 95% CI: 1.04-1.41; P=0.01). Primary graft failure was higher with cryopreservation (OR 1.48; 95% CI: 1.10-2.00; P=0.01) and the risk of chronic GVHD was lower (HR, 0.65; 95% CI: 0.50-0.84; P=0.001). In conclusion, while there was no negative impact of cryopreservation on OS, relapse was higher and DFS was lower. Fresh grafts are recommended as the pandemic related logistical hurdles resolve. Cryopreservation should be considered an option for patients when fresh grafts are not feasible.
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Non-Cryopreserved Peripheral Blood Stem Cell Graft for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma and Lymphoma Patients
Noiperm, P., Julamanee, J., Viboonjuntra, P., Lekhakula, A.
Annals of transplantation. 2023;28:e938595
Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) using cryopreserved grafts is time-consuming, expensive treatment, and may associated with dimethyl sulfoxide (DMSO) toxicity. Here, we assess the clinical utility and safety of non-cryopreserved peripheral blood stem cell graft in autologous HSCT. MATERIAL AND METHODS Medical data of multiple myeloma or lymphoma patients who underwent autologous non-cryopreserved HSCT were reviewed. RESULTS A total of 58 patients (40 myeloma and 18 lymphoma) were reviewed. The median myeloma and lymphoma CD34⁺ cell doses were 7.59 and 6.9 million/kg, respectively, with good viability after storage. The median times in neutrophil and platelet engraftment were 9 and 13 days and 11 and 14 days in myeloma and lymphoma, respectively. Only 5 patients in this cohort developed serious post-transplant complications. After transplantation, the cumulative incidence of relapse at 5 years was 34.4% in myeloma versus 19.1% in lymphoma patients. Notably, the mortality incidence rate rapidly increased within the first year and reached a plateau after 4 years, with cumulative incidence of 5.9% and 30.9% in myeloma and lymphoma, respectively. With a median follow-up time of 60 months, the median progression-free survival (PFS) and overall survival (OS) for lymphoma patients was 123.8 and 130 months, respectively. For the myeloma group, the median follow-up time was 38.6 months, the median PFS was 99.5 months, and OS was 157 months. CONCLUSIONS Non-cryopreserved HSCT is effective and safe. The long-term survival outcomes could be achieved by the shortening the duration of neutrophil and platelet engraftments and the complication rates are acceptable.
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Lower Incidence of Chronic GVHD Observed after Transplantation with Cryopreserved Unrelated Allogeneic Stem Cells
Maurer, K., Kim, H. T., Garrity, H. M., Liney, D., Cutler, C. S., Antin, J. H., Koreth, J., Ritz, J., Shapiro, R. M., Romee, R., et al
Blood advances. 2023
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8.
A French single-center experience on allogeneic stem cell transplant cryopreservation during severe acute respiratory syndrome coronavirus 2 pandemic
Laroye, C., Thilly, N., Gauthier, M., Luc, A., Latger-Cannard, V., Eschwege, V., Bensoussan, D., Pochon, C., Campidelli, A., Rubio, M. T., et al
Cytotherapy. 2023
Abstract
BACKGROUND AIMS Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a curative treatment for chemo-resistant hematological malignancies. Because of transport restriction imposed by the coronavirus disease 2019 pandemic, regulatory bodies and societies recommended graft cryopreservation before recipient conditioning. However, the freezing and thawing processes, including washing steps, might impair CD34+ cell recovery and viability, thereby impacting the recipient engraftment. Over 1 year (between March 2020 and May 2021), we aimed to analyze the results of frozen/thawed peripheral blood stem cell allografts in terms of stem cell quality and clinical outcomes. METHODS Transplant quality was evaluated by comparing total nucleated cells (TNCs), CD34+ cells and colony-forming unit-granulocyte/macrophage (CFU-GM)/kg numbers as well as TNC and CD34+ cell viabilities before and after thawing. Intrinsic biological parameters such as granulocyte, platelet and CD34+ cell concentrations were analyzed, as they might be responsible for a quality loss. The impact of the CD34+ cell richness of the graft on TNC and CD34 yields was evaluated by designing three groups of transplants based on their CD34 /kg value at collection: >8 × 10 (6)/kg, between 6 and 8 × 10(6)/kg and <6 × 10(6)/kg. The consequences of cryopreservation were compared in the fresh and thawed group by evaluating the main transplant outcomes. RESULTS Over 1 year, 76 recipients were included in the study; 57 patients received a thawed and 19 patients a fresh allo-SCT. None received allo-SCT from a severe acute respiratory syndrome coronavirus 2-positive donor. The freezing of 57 transplants led to the storage of 309 bags, for a mean storage time (between freezing and thawing) of 14 days. For the fresh transplant group, only 41 bags were stored for potential future donor lymphocyte infusions. Regarding the graft characteristics at collection, median number of cryopreserved TNC and CD34+ cells/kg were greater than those for fresh infusions. After thawing, median yields were 74.0%, 69.0% and 48.0% for TNC, CD34+ cells and CFU-GM, respectively. The median TNC dose/kg obtained after thawing was 5.8 × 10(8), with a median viability of 76%. The median CD34+ cells/kg was 5 × 10(6), with a median viability of 87%. In the fresh transplant group, the median TNC/kg was 5.9 × 10(8)/kg, and the median CD34+ cells/kg and CFU-GM/kg were 6 × 10(6)/kg and 276.5 × 10(4)/kg, respectively. Sixty-one percent of the thawed transplants were out of specifications regarding the CD34+ cells/ kg requested cell dose (6 × 10(6)/kg) and 85% of them would have had this dose if their hematopoietic stem cell transplant had been infused fresh. Regarding fresh grafts, 15.8% contained less than 6 × 10(6) CD34+ cells /kg and came from peripheral blood stem cells that did not reach 6 × 10(6) CD34+ cells /kg at collection. Regarding the factor that impaired CD34 and TNC yield after thawing, no significant impact of the granulocyte count, the platelet count or the CD34+ cells concentration/µL was observed. However, grafts containing more than 8 × 10 (6)/kg at collection showed a significantly lower TNC and CD34 yield. CONCLUSIONS Transplant outcomes (engraftment, graft-versus-host disease, infections, relapse or death) were not significantly different between the two groups.
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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.
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10.
Safety of Cryopreserved Stem Cell Infusion through a Peripherally Inserted Central Venous Catheter
Milczarek, S., Kulig, P., Zuchmańska, A., Baumert, B., Osękowska, B., Bielikowicz, A., Wilk-Milczarek, E., Machaliński, B.
Cancers. 2023;15(4)
Abstract
The management of patients undergoing stem cell transplantation requires a multipurpose central venous catheter (CVC) to facilitate drug administration, parenteral nutrition, transfusion of blood products, and collection of blood samples. Peripherally inserted central venous catheters (PICCs) appear to meet these requirements but are rarely used for stem cell infusion. We aimed to retrospectively assess the safety and feasibility of stem cell infusion through PICC and to evaluate its impact on transplantation kinetics. We retrospectively analyzed the outcomes of peripheral blood stem cell (PBSC) transplantation in patients receiving cryopreserved autologous or allogeneic PBSC by PICCs and compared the results with patients receiving transplants through a conventionally inserted central venous catheter (CICC). Despite statistically significant differences in CD34(+) dose, infusion rate, and total length of administration, the clinical outcomes of transplantation, exemplified by platelet and neutrophil engraftment, along with the length of hospitalization, were not affected by the prolonged infusion time and lower infusion velocity in the PICC group. Our study showed that the clinical outcomes of PBSC transplantation did not differ between the PICC and CICC groups, suggesting that both types of catheters can be implemented in a PBSC transplantation setting.