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1.
The effect of cryopreservation on engraftment kinetics in fully matched allogeneic stem cell transplantation: Real-life data and literature review
Ersal, T., Özkocaman, V., Yalçın, C., Orhan, B., Candar, Ö, Çubukçu, S., Koca, T. G., Pınar İ, E., Hunutlu, FÇ, Özkalemkaş, F.
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2023;:103821
Abstract
INTRODUCTION The standard approach for allogeneic stem cell transplantation (allo-SCT) is to administer donor cells on the same day as a fresh product to a patient who has been given a preparative regimen. The difficulty in collecting and transporting donor cells, especially during the COVID-19 pandemic, has made it essential to collect and cryopreserve the grafts before the recipient begins the transplant preparation regimen. However, the short- and long-term impacts of cryopreservation on transplant outcomes remain controversial. MATERIALS AND METHODS This retrospective study included 93 patients who underwent allo-SCT between January 2012 and August 2022 at the Stem Cell Transplant Unit of Bursa Uludag University Faculty of Medicine using frozen and fresh products of peripheral blood stem cells from a fully matched sibling donor. The effect of cryopreservation of donor grafts on engraftment kinetics was investigated. RESULTS Frozen and fresh products were used in 37 and 56 patients, respectively. The majority of patients had acute myeloid leukemia and acute lymphoblastic leukemia. The median age at transplantation was 41 years. Neutrophil engraftment time was similar between the two groups (median: 14 vs. 16 days, p = 0.393). Platelet engraftment time was longer in the frozen product group (median: 12 vs. 15 days, p < 0.001). There was no statistically significant difference between freezing time and viability. The acute graft-versus-host disease (GVHD) rate was 37.8 % in the frozen product group and 28.6 % in the fresh product group (p = 0.349). There was no significant difference between the two groups in terms of primary and secondary graft failure, chronic GVHD, 30-day chimerism, relapse, overall survival, progression-free survival, and nonrelapse mortality. CONCLUSION Having donor cells ready before transplantation significantly prevents donor-induced adverse events and provides confidence and practicality to both the clinician and the recipient. Allo-SCT with frozen products is a successful method that can be safely applied, especially when disruptions in donor-derived cell collection or transportation are foreseen.
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2.
Effects of extended transport on cryopreserved allogeneic hematopoietic progenitor cell (HPC) product quality and optimal methods to assess HPC stability
Reddy, O. L., Sall, M. T., Dinh, A., Cai, Y., Ongkeko, M., Arya, N., Wilder, J., Tran, M., Jin, P., Stroncek, D. F., et al
Transfusion. 2023
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Editor's Choice
Abstract
BACKGROUND Since the beginning of the COVID-19 pandemic, cryopreservation of hematopoietic progenitor cell (HPC) products has been increasingly used to ensure allogeneic donor graft availability prior to recipient conditioning for transplantation. However, in addition to variables such as graft transport duration and storage conditions, the cryopreservation process itself may adversely affect graft quality. Furthermore, the optimal methods to assess graft quality have not yet been determined. STUDY DESIGN AND METHODS A retrospective review was performed on all cryopreserved HPCs processed and thawed at our facility from 2007 to 2020, including both those collected onsite and by the National Marrow Donor Program (NMDP). HPC viability studies were also performed on fresh products, retention vials, and corresponding final thawed products by staining for 7-AAD (flow cytometry), AO/PI (Cellometer), and trypan blue (manual microscopy). Comparisons were made using the Mann-Whitney test. RESULTS For HPC products collected by apheresis (HPC(A)), pre-cryopreservation and post-thaw viabilities, as well as total nucleated cell recoveries were lower for products collected by the NMDP compared to those collected onsite. However, there were no differences seen in CD34+ cell recoveries. Greater variation in viability testing was observed using image-based assays compared to flow-based assays, and on cryo-thawed versus fresh samples. No significant differences were observed between viability measurements obtained on retention vials versus corresponding final thawed product bags. DISCUSSION Our studies suggest extended transport may contribute to lower post-thaw viabilities, but without affecting CD34+ cell recoveries. To assess HPC viability prior to thaw, testing of retention vials offers predictive utility, particularly when automated analyzers are used.
PICO Summary
Population
Cryopreserved hematopoietic progenitor cell products (HPCs) processed and thawed at a single centre in USA from 2007 to 2020 collected on site or by the National Marrow Donor Program (n=441)
Intervention
Products collected on site (n=158)
Comparison
Products collected through the National Marrow Donor Program (NMDP) (n=283)
Outcome
For HPC products collected by apheresis (HPC(A)), pre-cryopreservation and post-thaw viabilities, as well as total nucleated cell recoveries were lower for products collected by the NMDP compared to those collected onsite. However, there were no differences seen in CD34+ cell recoveries. Greater variation in viability testing was observed using image-based assays compared to flow-based assays, and on cryo-thawed versus fresh samples. No significant differences were observed between viability measurements obtained on retention vials versus corresponding final thawed product bags.
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3.
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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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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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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Cryopreservation of Growth Factor-Mobilized Peripheral Blood Stem Cells Does Not Compromise Major Outcomes after Allogeneic Hematopoietic Cell Transplantation - A Single Center Experience
Connelly-Smith, L., Gooley, T., Roberts, L., Mielcarek, M., Linenberger, M., Petersdorf, E., Sandmaier, B. M., Milano, F.
Transplantation and cellular therapy. 2023
Abstract
INTRODUCTION During the COVID-19 pandemic, cryopreservation of allogeneic donor stem cell products ensured availability of products at the start of conditioning for hematopoietic cell transplantation (HCT). Following recommendations from unrelated donor registries, including the National Marrow Donor Program (NMDP), many centers started to cryopreserve related donor peripheral blood stem cell (PBSC) products. Throughout the process, several centers have published outcomes with cryopreserved versus fresh products, some with conflicting results. Even though cryopreservation was initially considered only a temporary measure driven by the pandemic, potential advantages include greater flexibility of transplant timing. However, concern about detrimental effects of cryopreservation including increased risks of graft rejection, relapse and consequently mortality remained. OBJECTIVE The primary objective was to describe our center's experience comparing outcomes following PBSC transplantation with cryopreserved versus fresh grafts. METHODS This was an observational case study with retrospective review comparing cryopreserved grafts (N=213), to a recent historical cohort (controls) using fresh grafts (N=167). RESULTS In multivariable analyses, the adjusted hazard ratio (fresh vs. cryo) we for overall mortality was HR= 1.20 (95% confidence interval (CI), 0.79-1.82; p=0.40), for non-relapse mortality HR=0.99 (95% CI, 0.55-1.77; p=0.98), and for relapse HR=0.94 (95% CI, 0.60 -1.48; p=0.80). The adjusted hazard ratio for platelet engraftment was HR=1.31 (95% CI, 1.05-1.63; p=.02) and the odds ratio of grades III-IV acute GVHD was OR=1.75 (95% CI 1.01-3.04; p=.05) with fresh compared to cryopreserved grafts. CONCLUSION There was no demonstrable difference in the risk of chronic GHVD. Although longer-term follow-up is needed, these data provide preliminary reassurance that in the event of another pandemic or should the logistical need arise in individual patients, cryopreservation of PBSC products constitutes a reasonably safe alternative.
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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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Impact of cytoreduction and remission status on hematopoietic cell transplantation outcomes in pediatric myelodysplastic syndrome and related disorders
Wachter, F., Hebert, K., Pikman, Y., Yang, J., Shah, B., Bledsoe, J., Shimamura, A., Neuberg, D. S., Pollard, J. A., Lehmann, L. E.
Pediatric blood & cancer. 2023;:e30530
Abstract
BACKGROUND The role of cytoreduction prior to hematopoietic cell transplant (HCT) for patients with pediatric myelodysplastic syndrome (MDS) and related disorders remains unclear. PROCEDURE We performed a single-center retrospective analysis of pre-transplant disease management and subsequent HCT outcome for pediatric patients with MDS and related disorders who underwent HCT between 2010 and 2020. RESULTS Total 62 patients (median age 11 years) with idiopathic MDS (n = 16), MDS secondary to an underlying germline condition (n = 11), secondary acute myeloid leukemia (n = 9), myeloproliferative neoplasms (n = 8), and treatment-related myeloid neoplasms (n = 18) received an allogeneic HCT. Cytoreduction prior to HCT was performed in 30/62 (48%) patients; this subset of patients had higher risk disease characteristics, including a higher blast count on presentation. In the overall cohort, use of cytoreduction before HCT was associated with higher rates of relapse (cumulative incidence of relapse 24 months post HCT: 48.1% [27.5%-66.1%]) for those who received cytoreduction versus 16.6% (5.9%-32.1%) for those who did not (p = .03). There was a trend toward decreased overall survival (OS) for those patients who received cytoreduction (24 months post HCT 57.1% vs. 75.3%, respectively; p = .06). OS for patients who received cytoreduction and attained measurable residual disease (MRD) negativity prior to HCT was superior compared to those with persistent disease (24 months post HCT 63.9% [36%-81.2%] vs. 33.3% [7.8%-62.3%], respectively; p = .04). CONCLUSION Cytoreduction did not provide survival benefit in our overall cohort, but its increased use in children with higher risk disease impacted the analysis. Patients receiving cytoreduction and achieving MRD-negative status before HCT demonstrated improved OS compared to those with persistent disease.
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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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10.
Improving safety and outcomes after allogeneic hematopoietic cell transplantation: A single-centre experience
Salas, M. Q., Pasic, I., Remberger, M., Novitzky-Basso, I., Law, A. D., Lam, W., Chen, C., Kim, D. D. H., Michelis, F. V., Gerbitz, A., et al
Transplantation and cellular therapy. 2022
Abstract
The implementation of dual T-cell depletion comprising 4.5mg/kg of ATG, PTCY and CsA for reduced-intensity allogeneic HCT independent of donor source in 2015 significantly improved GVHD control at our Institution. Further advances were made between 2017-2020 in supportive care of allogeneic HCT recipients and were the subject of this study, with 651 adults included. Transplant outcomes were compared between patients transplanted during Period 1 (2017-2018) and Period 2 (2019-2020). Main changes implemented during study period were reduction of ATG dose from 4.5 to 2 mg/kg in matched unrelated donor transplants, abandoning of dual T-cell depletion in matched related donor transplants, combining dual T-cell depletion with myeloablative conditioning for selected patients, and reduction of the target therapeutic cyclosporine level from 200-400 ng/L to 150-250 ng/L. Other improvements included addition of ursodiol until day 100, implementation of a double responsible physician model, and personalized patient supportive care plan focused on activity and calorie intake. The reduction in intensity of GVHD prophylaxis provided comparable aGVHD and moderate-severe chronic GVHD between both time periods. Altogether the described improvements in transplant methodology and supportive care showed that compared to Period 1, patients transplanted in Period 2 had superior 1-y OS, RFS, NRM and showed a trend toward better GRFS, without an increase in relapse risk. This study reports the results of outcomes-directed improvements in transplant design, GVHD prophylaxis and supportive care, highlighting how transplant outcomes can be improved through careful modifications in response to meticulously monitored outcomes.