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Cryopreservation of Allogeneic Hematopoietic Cell Products During COVID-19 Pandemic: Graft Characterization and Engraftment Outcomes
Keyzner, A., Azzi, J., Jakubowski, R., Sinitsyn, Y., Tindle, S., Shpontak, S., Kwon, D., Isola, L., Iancu-Rubin, C.
Transplantation proceedings. 2023
Abstract
BACKGROUND The COVID-19 pandemic triggered the deployment of unfamiliar measures to safeguard successful allogeneic hematopoietic cell transplantation (allo-HCT). Among these measures, cryopreservation offered logistical benefits that could outlast the pandemic, including graft availability and timely clinical service. The purpose of this study was to evaluate graft quality and hematopoietic reconstitution in patients transplanted with cryopreserved allogeneic stem cell products during the COVID-19 pandemic. METHODS We evaluated 44 patients who underwent allo-HCT using cryopreserved grafts consisting of hematopoietic progenitor cells (HPC) apheresis (A) and bone marrow (BM) products at Mount Sinai Hospital. Comparative analyses of 37 grafts infused fresh during the one-year period preceding the pandemic were performed. Assessment of cellular therapy products included total nucleated cell and CD34+ cell enumeration, viability, and post-thaw recovery. The primary clinical endpoint was the evaluation of engraftment (absolute neutrophil count [ANC] and platelet count) and donor chimerism (presence of CD33+ and CD3+ donor cells) at day +30 and +100 post-transplant. Adverse events related to cell infusion were also analyzed. RESULTS Patient characteristics were comparable between the fresh and cryopreserved groups with 2 exceptions in the HPC-A cohort: the number of patients in the cryopreserved group that received haploidentical grafts was 6 times that in the fresh group, and the number of patients in the fresh group with a Karnofsky performance score >90 was double that in the cryopreserved group. The quality of HPC-A and HPC-BM products was not affected by cryopreservation, and all grafts met the release criteria for infusion. The pandemic did not affect the time between collection and cryopreservation (median, 24 hours) and time in storage (median, 15 days). Median time to ANC recovery was significantly delayed in recipients of cryopreserved HPC-A (15 vs 11 days, P = .0121), and there was a trend toward delayed platelet engraftment (24 vs 19 days, P = .0712). The delay in ANC and platelet recovery was not observed when only matched graft recipients were compared. Cryopreservation did not affect the ability of HPC-BM grafts to engraft and reconstitute hematopoiesis, and there was no difference in the rates of ANC and platelet recovery. Achievement of donor CD3/CD33 chimerism was not affected by cryopreservation of either HPC-A or HPC-BM products. Graft failure was observed in only 1 case, a recipient of cryopreserved HPC-BM. Three recipients of cryopreserved HPC-A grafts died before ANC engraftment from infectious complications. Remarkably, 22% of our studied population had myelofibrosis, and almost half received cryopreserved HPC-A grafts with no graft failure observed. Finally, patients receiving cryopreserved grafts were at a higher risk of infusion-related adverse events than those receiving fresh grafts. CONCLUSIONS Cryopreservation of allogeneic grafts results in adequate product quality with minimal impact on short-term clinical outcomes, except for an increased risk of infusion-related adverse events. Cryopreservation is a safe option in terms of graft quality and hematopoietic reconstitution with logistical benefits, but additional data are needed to determine long-term outcomes and assess whether this is a suitable strategy for at-risk patients.
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Cryopreserved versus fresh peripheral blood allogeneic stem cell transplantation outcomes in patients receiving post-transplant cyclophosphamide for graft-versus-host prophylaxis during the COVID-19 pandemic: a single center experience
Guo, M., Liu, J., Clark, P., Ahmad, S., Patel, R., Varela, J. C., Mori, S.
International journal of hematology. 2022;:1-10
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Editor's Choice
Abstract
BACKGROUND/OBJECTIVE Cryopreservation of grafts is not common practice in allogeneic hematopoietic stem cell transplant (HSCT) recipients. However, our center had to use cryopreserved cells for allogeneic HSCT during the COVID-19 pandemic to avoid delays in transplantation due to uncertainty regarding patient and donor exposures. STUDY DESIGN We retrospectively evaluated post-transplant engraftment and survival outcomes of adult patients who received cryopreserved versus fresh allografts during the COVID-19 pandemic. RESULTS Fifty-five patients with hematologic malignancies received either cryopreserved (n = 34) or fresh (n = 21) allogeneic HSCT using peripheral blood stem cells between January 2020 and December 2020. At a median follow-up time of 15 months, cryopreserved allograft recipients had significantly lower overall survival (OS) (p = 0.02). They also experienced significantly delayed neutrophil (p = 0.01) and platelet engraftments (p < 0.0001), as well as higher red blood cell transfusion-dependence after day + 60 (67.6% vs. 28.6%; p = 0.01). Significantly more cryopreserved allograft recipients received donor lymphocyte infusion than fresh allograft recipients (35.3% vs. 4.8%, p = 0.01). Neither relapse-free survival nor non-relapse mortality differed significantly between the two groups. CONCLUSION Cryopreservation of allografts in combination with post-transplant cyclophosphamide may negatively affect engraftment and OS outcomes in HSCT recipients.
PICO Summary
Population
Adults with haematologic malignancies undergoing allogeneic transplant during the COVID-19 pandemic, from a single centre in the USA (n=55)
Intervention
Cryopreserved allograft (n = 34)
Comparison
Fresh allograft (n = 21)
Outcome
At a median follow-up time of 15 months, cryopreserved allograft recipients had significantly lower overall survival (OS). They also experienced significantly delayed neutrophil and platelet engraftments, as well as higher red blood cell transfusion-dependence after day + 60 (67.6% vs. 28.6%). Significantly more cryopreserved allograft recipients received donor lymphocyte infusion than fresh allograft recipients (35.3% vs. 4.8%). Neither relapse-free survival nor non-relapse mortality differed significantly between the two groups.
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Neither COVID-19, nor cryopreservation, prevented allogeneic product infusion: A report from the National Marrow Donor Program
Farhadfar, N., Newman, J., Novakovich, J., Barten, J., Ndifon, E. T., Oakes, J., Cody, M., Pham, H. P., Auletta, J. J., Miller, J. P., et al
Frontiers in immunology. 2022;13:937900
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Editor's Choice
Abstract
BACKGROUND The Coronavirus Disease 2019 (COVID-19) pandemic in early 2020 has resulted in an unprecedented level of uncertainty and challenge for the stem cell donor registries. To address these challenges, rapid strategies were implemented by the National Marrow Donor Registry (NMDP) and its network partners. Herein, we aim to report the impact of the COVID-19 pandemic on the collection, utilization of grafts, and short-term outcomes of patients who received stem cell products from COVID-19-positive donors. METHODS NMDP data during the early phase (1 March 2020 through 1 May 2020) of the pandemic were compared to the later phase (1 March 2021 through 1 May 2021). Odds ratios were calculated to determine the impact of the pandemic on graft sources requested by transplant centers (TCs). The Kruskal-Wallis test was used to test the effect of the pandemic on the disease indication, volume of searches, and number of products not infused. RESULTS Although there was an initial decline in overall donor searches during the early phase of the pandemic, these numbers increased reaching pre-pandemic levels during the later phase. Urgent malignant diseases remained the most common indication for transplant in 2021. The pandemic necessitated cryopreservation of stem cell products due to transportation restrictions as well as clinical uncertainties in managing the virus. Cryopreserved grafts remained the most common requested grafts throughout the pandemic. In the later phase of the pandemic, the total numbers of requests for fresh grafts increased, mostly due to the increase in requests for fresh bone marrow (BM) grafts. As the pandemic continued, TCs became more accepting of cryopreservation, resulting in a reduction in the number of products not infused. Lastly, no short-term deleterious outcomes were noted among the patients who had stem cell products infused from a SARS-CoV-2-positive donor. CONCLUSION Throughout the pandemic, the NMDP and TCs worked tirelessly to ensure that patients would receive lifesaving grafts when needed. The data reported here, although limited by small numbers, illustrate that transplantation from donors with COVID-19 is feasible and safe.
PICO Summary
Population
Data on allogeneic transplants reported to the CIBMTR registry
Intervention
Donor collection and infusion dates for the period March 2020 – July 2020
Comparison
Donor collection and infusion dates for the period March 2021 – July 2021
Outcome
Although there was an initial decline in overall donor searches during the early phase of the pandemic, these numbers increased reaching pre-pandemic levels during the later phase. Urgent malignant diseases remained the most common indication for transplant in 2021. The pandemic necessitated cryopreservation of stem cell products due to transportation restrictions as well as clinical uncertainties in managing the virus. Cryopreserved grafts remained the most common requested grafts throughout the pandemic. In the later phase of the pandemic, the total numbers of requests for fresh grafts increased, mostly due to the increase in requests for fresh bone marrow grafts. As the pandemic continued, transplant centres became more accepting of cryopreservation, resulting in a reduction in the number of products not infused. Lastly, no short-term deleterious outcomes were noted among the patients who had stem cell products infused from a SARS-CoV-2-positive donor.
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Impact of microbial contamination of haematopoietic stem cells on post-transplant outcomes: A retrospective study from tertiary care centre in India
Garg, V., Kodan, P., Pushpam, D., Bakhshi, S., Kumar, L., Sharma, A., Gupta, G., Gupta, N.
Transfusion medicine (Oxford, England). 2021
Abstract
BACKGROUND Haematopoietic stem cells (HSC) may act as a source of infection for the recipient due to manipulation at multiple levels from collection to infusion. Due to the high risk of contamination cultures are usually taken during multiple steps. The clinical significance of microbial contamination of HSC on the post-transplant course and the role of prophylactic antibiotics is relatively unknown. AIMS AND METHODS The aim of our study is to investigate the incidence of microbial contamination of haematopoietic stem cell and to assess its impact on the post-transplant febrile neutropenia, engraftment kinetics, hospitalisation and day 100 mortality. Details of all patients admitted in the bone marrow transplantation unit of a tertiary care centre in India between January 2014 and December 2018 were collected from case records. RESULTS Of the 1306 stem cell harvests from 503 patients sent for culture, 17 harvests (1.3%) were found to have a culture positive report. Sixteen patients had undergone autologous transplant. Multiple myeloma was most common indication of HSC transplant followed by Non-Hodgkin Lymphoma (NHL). Twelve of 17 HSC cultures were positive at the time of infusion and five were positive at the time of harvest. The five HSC that were culture positive at the time of harvest were culture negative at the time of infusion. Gram-positive organisms were isolated in six cultures and gram-negative in rest. All patients developed febrile neutropenia post-transplantation between day 1 and day 7. The median time of onset of fever was day +5 (1-7), the median duration of fever was 4?days (2-7), the median duration of antibiotic use was 11?days (9-16). Median day for neutrophil engraftment was 11?days (9-16), the median day for platelet engraftment was 14?days (10-25) and median duration of hospitalisation was 15?days (12-78). All patients were alive at day 100 of transplant. CONCLUSION This study shows that there appears to be minimal impact of culture positive HSC on transplant related outcomes in terms of engraftment kinetics, duration of hospitalisation and day 100 mortality. Discarding of contaminated HSC may not be required, though on development of febrile neutropenia appropriate antibiotics should be administered based on sensitivity pattern of HSC culture. Larger prospective studies are needed to determine the clinical relevance of such contaminations. Emphasis should be laid on better infection control practices to minimise contamination rates.
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The role of early natural killer cell adoptive infusion before engraftment in protecting against human herpesvirus-6B encephalitis after naïve T-cell-depleted allogeneic stem cell transplantation
Gasior, M., Ferreras, C., de Paz, R., Bueno, D., Mozo, Y., Sisinni, L., Canizales, J. T., González, B., Olivas-Mazón, R., Marcos, A., et al
Transfusion. 2021
Abstract
BACKGROUND Naïve T-cell-depleted grafts have been employed as an ex vivo T-cell depletion (TCD) platform to prevent graft-versus-host disease (GvHD) and improve immune reconstitution by providing rapid donor memory T-cell reconstitution after allogenic hematopoietic stem cell transplantation (allo-HSCT). CD45RA(-) memory T cells confer protection against viruses such as cytomegalovirus, Epstein-Barr virus, and adenovirus; however, reports have shown an unexpectedly high incidence of human herpesvirus (HHV)-6B encephalitis among pediatric allo-HSCT patients. METHODS We report the first 18 consecutive allo-HSCT, 16 haplo-HSCT, and two human leukocyte antigen-matched related donors implanted with naïve TCD grafts. All donors were administered three cell products: first, a CD34(+) stem cell product; second, a CD45RA(+) TCD graft, followed by an adoptive natural killer (NK) cell infusion within 10?days after HSCT. The study's primary endpoint was the incidence of HHV-6B encephalitis. RESULTS Engraftment was achieved in 94.5% of cases; 2-year overall survival, event-free survival, and GvHD/relapse-free survival were 87.2% (95% CI 78.6-95.8), 67.3% (95% CI 53.1-81.5), and 64% (95% CI 50.5-78.1), respectively. HHV-6B reactivation occurred in 7 of the haplo-HSCT patients, six of who received a cell infusion with an NK/CD4 ratio <2. None of the patients developed encephalitis. CONCLUSIONS In this clinical study, we show that early adoptive NK cell infusion after a 45RA(+) TCD allo-HSCT graft is safe and can prevent HHV-6B encephalitis. We recommend infusing adoptive NK cells after allo-HSCT using CD45RA(+) TCD grafts.
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Impact of COVID-19 on peripheral stem cell collection and preservation at a hematopoietic cell transplant center in India: Experience 2020
Javed, R., Roychowdhury, M., Bhave, S., Nag, A., Kumar, J., Radhakrishnan, V., Bhattacharya, S., Mishra, D. K., Ghara, N., Rs, R., et al
Blood cell therapy. 2021;4(4):84-87
Abstract
The prevailing corona virus disease 19 (COVID-19) pandemic has adversely affected the healthcare services globally. Hematopoietic cell transplantation (HCT) is considered as the preferred treatment option for several hematological malignancies, and HPC collection facilities have to function continuously along with implementing safety measures. Based on the national and international guidelines, we implemented additional measures and modifications to our standard operating procedure (SOP) to ensure secure HPC collection from patients as well as donors. Here, we report our experience with HPC collection and processing from 1st January, 2020 until 31st December, 2020. We collected 59 HPC products through apheresis and 41 cryopreservation procedures. Compared to 2019, there was a 33% decrease in the number of HPC transplants and 31% reduction in HPC collection procedures. However, we report an 86% (13 procedures) increase in the cryopreservation of HPC products from related donors, as several organizations recommend cryopreservation of HPC products. We report our institutional experience to better understand the impact of COVID-19 on HCT services in a tertiary care center in the developing world. It may also help in being prepared for any future waves of COVID-19 cases.
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Cryopreservation of unrelated donor hematopoietic stem cells: the right answer for transplantations during the COVID-19 pandemic?
Fernandez-Sojo, J., Azqueta, C., Valdivia, E., Martorell, L., Medina-Boronat, L., Martínez-Llonch, N., Torrents, S., Codinach, M., Canals, C., Elorza, I., et al
Bone marrow transplantation. 2021;:1-8
Abstract
Cryopreservation was recommended to ensure continuity of unrelated donor (UD) hematopoietic stem cell transplantation (HSCT) during COVID-19 pandemic. However, its impact on clinical outcomes and feasibility was not well known. We compared 32 patients who underwent UD HSCT using cryopreserved peripheral blood stem cells (PBSC) during the COVID-19 pandemic with 32 patients who underwent UD HSCT using fresh PBSC in the previous period. Median neutrophil engraftment was 17.5 and 17.0 days with cryopreserved and fresh grafts, respectively. Non-significant delays were found in platelet recovery days (25.5 versus 19.0; P?=?0.192) and full donor chimerism days (35.0 and 31.5; P?=?0.872) using cryopreserved PBSC. The rate of acute graft-versus-host disease at 100 days was 41% (95% CI [21-55%]) in cryopreserved group versus 31% (95% CI [13-46%]) in fresh group (P?=?0.380). One-hundred days progression-relapse free survival and overall survival did not differ significantly. During COVID-19 pandemic, six frozen UD donations were not transfused and logistical and clinical issues regarding cryopreservation procedure, packaging, and transporting appeared. In summary, UD HSCT with cryopreserved PBSC was safe during this challenging time. More efforts are needed to ensure that all frozen grafts are transplanted and cryopreservation requirements are harmonized.
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Prevalence and significance of bacterial contamination of autologous stem cell products
Damonti, L., Buetti, N., Droz, S., Bacher, U., Pabst, T., Taleghani, B. M., Baerlocher, G. M., Marschall, J.
The Journal of hospital infection. 2021
Abstract
There is limited and conflicting information on the prevalence of the contamination of hematopoietic stem and progenitor cell products (HPCPs) and their optimal management remains unclear. We reviewed the microbial surveillance data of HPCPs collected between 01/2002 and 12/2019 for autologous transplantation at our institution to determine the prevalence of microbial contamination and the potential infectious complications among recipients. Among 3935 HPCPs, 25 (0.6%) were contaminated. Ultimately, 22 patients received contaminated grafts, with a preemptive antimicrobial therapy initiated in 6/22. None developed subsequent infectious complications. Our data suggest that microbial contamination of autologous HPCPs and associated adverse outcomes are rare.
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Variable CD34+ recovery of cryopreserved allogeneic HPC products: transplant implications during the COVID-19 pandemic
Purtill, D., Antonenas, V., Chiappini, P., Tong, D., O'Flaherty, E., Bajel, A., Kabani, K., Larsen, S., Tan, S., Hutchins, C., et al
Blood advances. 2020;4(17):4147-4150
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Abstract
Donor registries and transplantation societies recommend cryopreservation of unrelated donor hemopoietic progenitor cell (HPC) products before the recipient commences conditioning therapy to mitigate the donor and travel risks associated with the COVID-19 pandemic. However, little is known regarding the postthaw quality of such allogeneic products or the effect of precryopreservation storage and processing on these characteristics. We investigated the postthaw CD34+ cell recovery and viability of 305 allogeneic HPC products cryopreserved at 9 laboratories across Australia. Median postthaw CD34+ cell recovery was 76% and ranged from 6% to 122%. Longer transit time before cryopreservation, white cell count (WCC) during storage, and complex product manipulation before cryopreservation were independently associated with inferior postthaw CD34+ cell recovery. Longer precryopreservation transit time and WCC were also associated with inferior postthaw CD34+ cell viability. We conclude that although postthaw CD34+ cell recovery and viability of cryopreserved allogeneic HPC is generally acceptable, there is a significant risk of poor postthaw product quality, associated with prolonged storage time, higher WCC, and complex product manipulation precryopreservation. Awareness of expected postthaw recovery and practices that influence it will assist collection, processing, and transplant centers in optimizing outcomes for transplant recipients.
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Transplantation of Ex Vivo Expanded Umbilical Cord Blood (NiCord) Decreases Early Infection and Hospitalization
Anand, S., Thomas, S., Hyslop, T., Adcock, J., Corbet, K., Gasparetto, C., Lopez, R., Long, G. D., Morris, A. K., Rizzieri, D. A., et al
Biology of Blood & Marrow Transplantation. 2017;23(7):1151-1157
Abstract
Delayed hematopoietic recovery contributes to increased infection risk following umbilical cord blood (UCB) transplantation. In a Phase 1 study, adult recipients of UCB stem cells cultured ex vivo for 3 weeks with nicotinamide (NiCord) had earlier median neutrophil recovery compared with historical controls. To evaluate the impact of faster neutrophil recovery on clinically relevant early outcomes, we reviewed infection episodes and hospitalization during the first 100 days in an enlarged cohort of 18 NiCord recipients compared with 86 standard UCB recipients at our institution. The median time to neutrophil engraftment was shorter in NiCord recipients compared with standard UCB recipients (12.5 days versus 26 days; P<.001). Compared with standard UCB recipients, NiCord recipients had a significantly reduced risk for total infection (RR, 0.69; P=.01), grade 2-3 (moderate to severe) infection (RR, 0.36; P<.001), bacterial infection (RR, 0.39; P=.003), and grade 2-3 bacterial infection (RR, 0.21; P=.003) by Poisson regression analysis; this effect persisted after adjustment for age, disease stage, and grade II-IV acute GVHD. NiCord recipients also had significantly more time out of the hospital in the first 100 days post-transplantation after adjustment for age and Karnofsky Performance Status (69.9 days versus 49.7 days; P=.005). Overall, transplantation of NiCord was associated with faster neutrophil engraftment, fewer total and bacterial infections, and shorter hospitalization in the first 100 days compared with standard UCB transplantation. In conclusion, rapid hematopoietic recovery from an ex vivo expanded UCB transplantation approach is associated with early clinical benefit. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.