Research ArticleClinical Studies
Open Access

The Impact of Cryopreservation on Hematopoietic Stem Cell Engraftment and Post-transplant Outcome During the COVID-19 Pandemic

ANNA STRZELEC, NATALIA GAWLIK-RZEMIENIEWSKA, ANNA KLIMA, KAROLINA PANEK and GRZEGORZ HELBIG
In Vivo May 2024, 38 (3) 1271-1277; DOI: https://doi.org/10.21873/invivo.13565

Abstract

Background/Aim: The COVID-19 pandemic has had a significant impact on the current management of allotransplanted patients in whom fresh hematopoietic stem cells (HSCs) were replaced by cryopreserved ones. The aim of the study was to determine the efficacy and safety of cryopreserved HSCs when compared with the fresh ones. Patients and Methods: A retrospective analysis of 254 allogeneic stem cell transplantations (HSCT) procedures performed between 2020-2021 included the following donors: matched related (MRD; n=68), matched unrelated (MUD; n=148) and haploidentical (HID; n=38). 50% of patients (non-cryo group) received fresh grafts, whereas the remaining patients (cryo group) were transplanted with cryopreserved cells. Results: No differences in terms of median days to neutrophil [MRD/MUD/HID cryo- and non-cryo groups: 17 vs. 16 (p=0.27), 19 vs. 18 (p=0.83), 22 vs. 22 (p=0.83) days, respectively] and platelet [MRD/MUD/HID cryo- and non-cryo groups: 14 vs. 14 (p=0.25), 17 vs. 17 (p=0.33), 21 vs. 19 (p=0.36) days, respectively] engraftments were demonstrated. Among MUD graft recipients, platelet engraftment rates were 81% in the cryo- and 96% in the non-cryo group (p=0.01). OS rates were comparable at 1 year after HSCT between MRD/MUD/HID cryo- and non-cryo groups: 53% vs. 60% (p=0.54), 60% vs. 66% (p=0.5), 50% vs. 41% (p=0.56), respectively. Conclusion: During the COVID-19 pandemic, cryopreserved HSCs did not have a negative impact on median engraftment time and OS when compared to fresh HSCs. In the MUD group, platelet engraftment rate was lower in cryopreserved HSC recipients.

Key Words:

According to the World Health Organization (WHO), the coronavirus disease 19 (COVID-19) pandemic began in March 2020 (1) and introduced restrictions not only into daily life, but also into routine clinical practice. The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the organization of the healthcare system, including hematopoietic stem cell transplantation (HSCT) procedures, has been unquestionable (2). Despite the lack of strong evidence of SARS-CoV-2 transmission via blood products, several regulations were implemented to mitigate the transmission of SARS-CoV-2 (3). Therefore, in view of the necessity of material withdrawal and to reduce potential risks relating to graft transportation, the principle of cryopreservation of material from unrelated donors was implemented (4-6).

HSCT is a potentially curative treatment option for patients with selected hematological disorders, albeit associated with high morbidity and mortality rates (7-9). In patients undergoing HSCT, the fresh hematopoietic stem cells (HSCs) should be infused as soon as possible after collection. However, COVID-19 pandemic changed this paradigm causing a need for cryopreservation of grafts before the commencement of conditioning. Proper preparation and storage of HSCT products becomes a prerequisite for preserving their quality and functionality, crucial for achieving engraftment and effective hematopoiesis, which further reduces the risk of infection and death caused by prolonged neutropenia (10-13). Cryopreservation of HSCs, using dimethyl sulfoxide (DMSO), remains a widely used and safe procedure, enabling the long-term storage of material in liquid nitrogen tanks (14). Of note, this process can be detrimental to the cells during the slow-freezing, which is necessary to limit the formation of intracellular ice crystals, the risk of excessive dehydration and osmotic stress occurs (15).

The purpose of the study was to determine the safety profile of cryopreservation, storing and thawing of HSCs by evaluating the effects of these processes on the engraftment potential, compared to non-cryopreserved HSCs, along with the overall survival (OS) of graft recipients. Here we present the results of single-center analysis of 254 HSCT performed between January 2020 and December 2021.

Patients and Methods

Patient characteristics. Two hundred and fifty-two adult patients (age >18 years old), who underwent a total of 254 transplant procedures between January 2020 and December 2021 were included into this study. A total of 127 HSCTs were performed using cryopreserved material (cryo group) and 127 using non-cryopreserved material (non-cryo group). The patients were given informed consent before entering the study. The material for HSCT was peripheral blood stem cells (PBSCs). The entire study group was divided into three cohorts, according to the type of donor: 1) matched related donor (MRD) graft recipients (n=68; 27%), 2) matched unrelated donor (MUD) graft recipients (n=148; 58%), 3) haploidentical donor (HID) graft recipients (n=38; 15%).

Definitions. Engraftments were defined as follows: 1) absolute neutrophil count (ANC) above or equal to 0.5 g/l on three consecutive days, and 2) platelet count above or equal to 20 g/l (without platelet transfusion support) on three consecutive days (16). OS was defined as the time from HSCT to death from any cause or the date of last follow-up.

Graft preparation. HSCs were collected from the granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood (PB) of healthy donors by leukapheresis. Material intended for cryopreservation was diluted to concentrations of 50-250 g/l using 5% DMSO and plasma replacement fluid, then cryopreserved in a controlled rate freezer within no more than 72 h after collection. The final product was stored in the vapor phase of liquid nitrogen at ≤–150°C in a cryogenic tank. On the day of transplantation, the HSCs were transported at ≤–150°C, then thawed at 37°C for 5 min and immediately infused. Cell viability was tested microscopically using trypan blue and was determined >80%.

Non-cryopreserved material was stored and transported at 2-8°C, then at room temperature directly before infusion, which occurred within no more than 72 h after collection. Cell viability was tested microscopically using trypan blue and was determined >80%.

Statistics. STATISTICA 13.3 (StatSoft Europe GmbH, Hamburg, Germany) and XLSTAT (Lumivero, Denver, CO, USA) software were utilized for statistical analysis. The normality of distributions was assessed using the Shapiro-Wilk test. Since the results did not adhere to a normal distribution, they are presented using median. For evaluating the statistical significance of distributions, the non-parametric Mann-Whitney U-test was applied for continuous variables. Chi-square test of independence was performed for categorical variables and in selected cases, Yates’ continuity correction was implemented. The Kaplan-Meier method, along with a log-rank test, was employed to compare OS and hematological recovery. The Cox proportional hazard model determined hazard ratio (HR) with a 95% confidence interval (CI) for survival time. The significance level for all analyses was set at p<0.05.

Results

Distribution of patients’ characteristics in cryo- and non-cryo group. Statistical analysis of distribution of patient characteristics showed that the analyzed groups were significantly different in terms of donor type (79% of MUD in the cryo group vs. 37% in the non-cryo group; p<0.001), storage time of the graft (median storage time in the cryo group was 11 days vs. 0 in the non-cryo group; p<0.001) as well as year of transplantation performed (57% of transplantations performed in 2020 in the cryo group vs. 41% in the non-cryo group and 54% of transplantations performed in 2021 in the cryo group vs. 75% in the non-cryo group; p=0.01). The details are presented in Table I.

View this table:
Table I.

Distribution of patients' characteristics in cryo- and non-cryo group.

Engraftment in the MRD group. Twenty patients received a cryopreserved graft whereas 48 patients were transplanted with fresh HSCs. Neutrophil engraftment was achieved by 90% (95%CI=77-100%) of patients in the cryo group vs. 98% (95%CI=94-100%) in the non-cryo group (p=0.13). Platelet engraftment was achieved by 95% (95%CI=85-100%) of patients in the cryo group vs. 98% (95%CI=94-100%) in the non-cryo group (p=0.25).

After eliminating two cases, due to death within 14 days after HSCT (one patient in each group), 95% of patients in the cryo group achieved an ANC ≥0.5 g/l by day 28 after HSCT vs. 98% in the non-cryo group (p=0.88).

Considering patients who were engrafted, median neutrophil engraftment was 17 days (range=13-25 days) in the cryo group vs. 16 days (range=10-29 days) in the non-cryo group (p=0.27). Median platelet engraftment was 14 days (range=10-29 days) in the cryo group vs. 14 days (range=8-27 days) in the non-cryo group (p=0.25).

Engraftment in MUD group. One hundred and one patients received a cryopreserved graft and 47 were immediately grafted from MUD. Neutrophil engraftment was achieved by 95% (95%CI=91-99%) of patients in the cryo group vs. 96% (95%CI=90-100%) in the non-cryo group (p=0.92). Platelet engraftment was achieved by 81% (95%CI=74-89%) of patients in the cryo group vs. 96% (95%CI=90-100%) in the non-cryo group (p=0.01). The cumulative incidence for platelet engraftment is shown in Figure 1.

Figure 1.
Figure 1.

Comparison of platelet engraftment in matched unrelated donor (MUD) cryo- and non-cryo groups.

After eliminating four cases, due to death within 14 days after infusion (two patients in each group), 90% of patients in the cryo group achieved an ANC ≥0.5 g/l by day 28 after HSCT vs. 89% in the non-cryo group (p=0.92).

Considering patients who achieved engraftment, median neutrophil engraftment was 19 days (range=10-35 days) in the cryo group vs. 18 days (range=12-41 days) in the non-cryo group (p=0.83). Median platelet engraftment was 17 days (range=8-36 days) in the cryo group vs. 17 days (range=10-34 days) in the non-cryo group (p=0.33).

Engraftment in HID group. Six patients received previously cryopreserved material, while 32 patients were given a fresh graft. Neutrophil engraftment was achieved by 67% (95%CI=29-100%) of patients in the cryo group vs. 84% (95%CI=72-97%) in the non-cryo group (p=0.24). The same statistic applies to achieving an ANC ≥0.5 g/l by day 28 after HSCT. Platelet engraftment was achieved by 50% (95%CI=10-90%) of patients in the cryo group vs. 69% (95%CI=53-85%) in the non-cryo group (p=0.47).

Considering patients who were engrafted, median neutrophil engraftment was 22 days (range=22-27 days) in the cryo group vs. 22 days (range=12-28 days) in the non-cryo group (p=0.83). Median platelet engraftment was 21 days (range=14-23 days) in the cryo group vs. 19 days (range=12-34 days) in the non-cryo group (p=0.36). Median engraftment times and sample sizes are shown in Table II.

View this table:
Table II.

Comparison of survival rates stratified by patient characteristics.

Post-transplant outcome. One-year OS rates among graft recipients from MRD were 53% (95%CI=31-76%) in the cryo group vs. 60% (95%CI=47-74%) in the non-cryo group (p=0.54) and no significant difference in death rates between the analyzed groups was demonstrated (HR=0.8; 95%CI=0.38-1.68; p=0.55). The median follow-up for surviving patients in this group was 33 months (range=23-46 months).

One-year OS rates among graft recipients from MUD were 60% (95%CI=51-70%) in the cryo group vs. 66% (95%CI=52-79%) in the non-cryo group (p=0.5) and no significant difference in death rates between the analyzed groups was demonstrated (HR=0.83; 95%CI=0.48-1.44; p=0.51). The median follow-up for surviving patients in this group was 32 months (range=22-46 months).

One-year OS rates among graft recipients from HID were 50% (95%CI=10-90%) in the cryo group vs. 41% (95%CI=24-58%) in the non-cryo group (p=0.56). The median follow-up for patients alive in this group was 39 months (range=26-46 months).

Discussion

As cryopreservation of HSCs has proven to be a safe procedure allowing long-term storage for autologous HSCT (17-20), its potential implementation in allogeneic HSCT cases has gained attention during the COVID-19 pandemic. Proper cryopreservation is critical to preserving the functionality of HSCs as it carries the risk of diminishing material quality, subjecting it to a considerable number of regulatory standards. It is crucial to recognize that the appropriate management of the cell storage system requires adaptation to the latest requirements and the involvement of experienced professionals (12, 13, 21). The use of DMSO, which is an intracellular cryoprotectant, limits deformation and cell damage, but it exhibits cell toxicity after thawing. Moreover, it can be responsible for some adverse reactions observed clinically, e.g., gastrointestinal and cardiovascular ones, however they are usually mild and transient (15, 22). Current guidelines advise reducing the concentration of DMSO in the final cell mixture to 5%, which limits toxicity without adversely affecting engraftment potential (23). However, inadequate preparation of HSCs poses a risk of excessive cell damage, and thus post-thawing necrosis and apoptosis. This, in turn, entails the danger of poor engraftment and a weakened graft-vs.-leukemia (GVL) effect (24). CD3+ cells appear to be particularly sensitive to the cryopreservation and thawing process, even more so if they are derived from non-mobilized peripheral blood, which is especially relevant for the donor lymphocyte infusion (DLI) procedure (25).

The use of cryopreserved material for allogeneic HSCT was not widespread prior to the COVID-19 pandemic, as the standard practice involved the use of fresh HSCs, however, the percentage of cryopreserved materials significantly increased after 2020 (26). Nevertheless, further studies confirming the effectiveness of cryopreserved cell transplants are warranted. In our research, the results pertaining to neutrophil engraftment and OS in the cryo- and non-cryo groups, regardless of donor type, showed no statistically significant differences. This suggests the safety of both choices and affirms that the cryopreserved grafts met the quality criteria. Also, platelet recovery in the cryo- and non-cryo groups, when analyzed for MRD and HID, showed no statistically significant differences. In contrast, in the MUD group, platelet engraftment was more efficient in the fresh HSC recipients. No statistically significant difference between cryopreserved and fresh HSCs in terms of median days to neutrophil and platelet engraftment was demonstrated. It is important to note a limitation of the study, namely the low number of HID cases in the cryo group. A major HLA disparity is one of the key factors that can affect engraftment and OS, for this reason studies on a larger group of HID cryopreserved graft recipients are advisable (27-30). Moreover, in our center, throughout the COVID-19 pandemic era, most grafts from related donors were transplanted fresh and grafts from unrelated donors were previously cryopreserved.

Facchin et al. (31) presented the outcomes of 54 HSCT from MUD, showing no statistically significant differences in median engraftment time or OS among recipients of fresh and cryopreserved grafts. In the analysis by Purtill et al. (32), which focused on 191 cryopreserved transplantations performed in 2021, the median engraftment time was 17 days and did not differ significantly from the median engraftment time of fresh grafts one year earlier. A pandemic-era study reported by Kanda et al. (33) included 112 patients who underwent allogeneic HSCT from cryopreserved cells. The incidence of neutrophil engraftment on day 28 was 91.1% and the absence of HLA mismatch was associated with faster neutrophil engraftment. After excluding three patients, due to early death, all patients achieved neutrophil engraftment within 60 days after HSCT.

Nevertheless, the data published by transplant centers are not conclusive. Results of allogeneic HSCT from 72 MRD were presented by Dagdas et al. (34). Their analysis indicated a longer neutrophil engraftment time in the group that received frozen material (14 days vs. 16 days; p=0.006). Ersal et al. (35) also presented the results of 93 transplants from an MRD, showing a difference in platelet engraftment to the disadvantage of cryopreserved products (12 vs. 15 days; p<0.001). Maurer et al. (36) found that cryopreserved MUD transplant recipients had delayed platelet engraftment (21 vs. 18 days; p=0.044) and impaired white blood cell and T-cell reconstitution at day 30. Interestingly, Capelle et al. (37) analyzed the effect of peripheral blood mononuclear cell (PBMC) cryopreservation, by evaluating human T cell subsets (CD4 conventional T cells, regulatory T cells and CD8 total). They noted a decrease in the detection of markers corresponding to effector functions, senescence, activation, and others, including those critical for immune exhaustion. Since no differences were observed in the frequency of CD4, CD8, and regulatory T cells, the authors pointed out that this decrease in markers may not be due to lower expression but a change in the epitopes and thus less detection using flow cytometry.

Conclusion

Cryopreservation of HSCs for allogeneic HSCT is not the standard of care, despite gaining importance in the COVID-19 pandemic era. Transplant outcomes during this period contribute valuable knowledge about the impact of HSC cryopreservation on engraftment potential, shedding light on the safety and viability of this alternative. The results we presented indicate a satisfactory safety profile, in terms of engraftment and OS, for cryopreservation of HSCs prior to transplantation if compared to fresh HSCs. Nevertheless, it should be kept in mind that this process is a multi-step, complex procedure with additional risks of delayed engraftment. Further research is desirable, especially with longer-term follow-up and a larger study group, particularly regarding those undergoing HSCT from a HID.

Footnotes

  • Authors’ Contributions

    GH: project idea, critical review with correction. NGR, AK, KP: collection and interpretation of clinical data, critical revision. AS: writing of the review, collection, and interpretation of clinical data.

  • Funding

    None.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare in relation to this study.

  • Received January 19, 2024.
  • Revision received February 23, 2024.
  • Accepted February 26, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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The Impact of Cryopreservation on Hematopoietic Stem Cell Engraftment and Post-transplant Outcome During the COVID-19 Pandemic
ANNA STRZELEC, NATALIA GAWLIK-RZEMIENIEWSKA, ANNA KLIMA, KAROLINA PANEK, GRZEGORZ HELBIG
In Vivo May 2024, 38 (3) 1271-1277; DOI: 10.21873/invivo.13565
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