Fresh Versus Cryopreserved Allograft Outcomes in Peripheral Blood Stem Cell Transplantations

Background: The emergence of the COVID-19 pandemic saw an increased use of cryopreserved (cryo) peripheral blood (PB) grafts for allogeneic hematopoietic stem cell transplantation (HSCT). Outcomes of patients receiving either fresh or cryo grafts have yielded heterogeneous results. Herein, we retrospectively compared the outcomes of patients receiving fresh and cryo grafts at a single center.(Table Presented)Methods: Between 2019 and 2021, we reviewed data from 380 patients;167 (44%) received a fresh, and 213 (56%) received a cryo graft. Patients underwent myeloablative or nonmyeloablative HSCT from either matched or mismatched, related or unrelated donors. Cell doses were determined by number of donor cells collected and recipient weight at infusion. Engraftment, disease risk (DR) and acute GVHD were classified based on established criteria. Donor chimerism was collected at approximately day 28 and day 80 after HSCT. Unadjusted and adjusted estimates of overall survival (OS), relapse, and non-relapse mortality (NRM) as a function of time were obtained. The adjusted odds (grades III-IV acute GVHD) and the adjusted cause-specific hazard of failure (all other outcomes) were compared between the 2 groups. with the use of logistic (Figure Presented) or Cox regression, respectively. These models were adjusted for various factors known to be associated with each outcome. Result(s): The characteristics of patients between the 2 groups are shown in Table 1. There was a higher proportion of patients with high/very high DR in the fresh graft group (Table 1). Median time to neutrophil engraftment was 17 and 18 days in fresh vs. cryo, respectively. The adjusted hazard ratio (HR) of neutrophil engraftment (fresh vs. cryo) was 1.07 (95% CI, 0.86-1.34, p=0.54). Median time to platelet engraftment was 13 and 15 days, respectively, and the adjusted HR of platelet engraftment was 1.32 (1.06-1.65, p=0.01). Day 28 chimerism data were available for 272 patients (113 fresh and 159 cryo). At day 28, donor CD3 chimerism was below 50% in 5 out of 113 (4.4%) and 17 out of 159 (10.7%) patients receiving fresh and cryo grafts, respectively (p= 0.06). At day 80, 3 out of 121 (2.5%) patients in the fresh group and 4 out of 165 (2.4%) in the cryo group had CD3 chimerism below 50%. The adjusted HRs (fresh vs. cryo) for death and NRM were 0.83 (0.54-1.28, p=0.40) and 0.71 (0.38-1.33, p=0.29), respectively (Figures 1 and 2). The adjusted HR for relapse was 0.65 (0.42-0.99, p=0.05) (Figure 3). The adjusted odds ratio (fresh vs. cryo) for grades III-IV GVHD was 1.65 (0.94-2.9, p=0.07). Conclusion(s): In this single-center retrospective study we observed numerically better outcomes with fresh grafts relative to cryo grafts for all examined endpoints with the exception of grades III-IV aGVHD, although none of the differences were definitive with the possible exception of relapse and platelet engraftment. Further studies are needed to confirm our observations.Copyright © 2023 American Society for Transplantation and Cellular Therapy

Impact of COVID-19 pandemic on collection of allogeneic hematopoietic stem cells

Introduction: COVID-19 pandemic brought challenges in the organization of hematopoietic stem cell (HSC) transplantation. Availability of HSCs was decreased due to donor infection and transport limitations. Accordingly, a series of measures was introduced to ensure the protection of patients and donors and availability of transplants during the pandemic. The goal of this study was to show the impact of COVID-19 pandemic on the collection of allogeneic HSCs in University Hospital Centre (UHC) Zagreb. Methods: We conducted a retrospective analysis for the period from March 1, 2020, to June 30, 2021. The data were collected from hospital computer database and meeting reports of the HSC Transplantation Committee of UHC Zagreb. Results: In the reported period peripheral blood stem cells (PBSC) were preferred, except when bone marrow (BM) transplantation was strongly indicated. Allogeneic HSC grafts were cryopreserved before conditioning to ensure availability on the day of transplantation. Thirteen patients were excluded from the program due to COVID-19 infection. HSCs were collected from related and unrelated donors from the Croatian HSC Donor Registry and World Marrow Donor Assocciation for the total of 135 patients. All 17 (12.5%) harvested BM grafts were transplanted. Sixteen patients were transplanted with PBSC instead of BM. Out of the collected PBSC 94.1% were transplanted but in 17 patients transplantations were delayed due to COVID-19 infection of the donor and/or the patient. Of the total 118 PBSC transplants 100 (84.7%) were cryopreserved in 540 cryo bags. Seven (5.9%) cryopreserved grafts have not been infused because of the progression of the main disease (5), COVID-19 infection of the patient (1) and poor product viability (1). Conclusion: COVID-19 pandemic adversely impacted HSC collection and transplantation with many organizational and logistical challenges. Cryopreservation of allogeneic grafts enabled efficient management of the transplantation programs but was accompanied with the risk of not infusing some grafts, which exposed donors to unnecessary risks and increased the cost of treatment. © 2022 Hrvatski Lijecnicki Zbor. All rights reserved.

Effect of Cryopreservation in Unrelated Bone Marrow and Peripheral Blood Stem Cell Transplantation in the Era of the COVID-19 Pandemic: An Update from the Japan Marrow Donor Program.

During the COVID-19 pandemic, donor grafts are frequently cryopreserved to ensure that a graft is available before starting a conditioning regimen. However, there have been conflicting reports on the effect of cryopreservation on transplantation outcomes. Also, the impact of cryopreservation may differ in bone marrow (BM) transplantation (BMT) and peripheral blood stem cell (PBSC) transplantation (PBSCT). In this retrospective study, we analyzed the clinical data of both cryopreserved unrelated BMTs (n = 235) and PBSCTs (n = 118) and compared these with data from a large control cohort without cryopreservation including 4133 BMTs and 720 PBSCTs. Among the patients with cryopreserved grafts, 10 BMT recipients (4.3%) and 3 PBSCT recipients (2.5%) did not achieve neutrophil engraftment after transplantation, including 4 of the former and all 3 of the latter who died early before engraftment. In a multivariate analysis, cryopreservation was not associated with neutrophil engraftment in BMT but significantly delayed neutrophil engraftment in PBSCT (hazard ratio [HR], .82; 95% confidence interval [CI], .69 to .97; P = .023). There was an interaction with borderline significance between cryopreservation and the stem cell source (P = .067). Platelet engraftment was delayed by cryopreservation after both BMT and PBSCT. Only 2 cryopreserved grafts (<1%) were unused during the study period. The cryopreservation of unrelated donor BM and PBSC grafts is associated with a slight delay in neutrophil and platelet engraftment but an acceptable rate of graft failure. PBSC grafts may be more sensitive to cryopreservation than BM grafts. Cryopreservation is a reasonable option during COVID-19 pandemic, provided that the apheresis and transplantation centers are adept at cryopreservation. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Post-Transplant Cyclophosphamide, Abatacept, and Short Course of Tacrolimus Combination (CAST) Is Safe and Seems Highly Effective in Preventing Graft-Versus-Host Disease Following Haploidentical Peripheral Blood Stem Cell Transplantation

The introduction of post-transplant cyclophosphamide (PTCy) has circumvented the need for T-cell depletion following haploidentical stem cell transplantation (SCT). By expanding the donor pool for patients from certain ethnic minorities, this has addressed to some degree an important health care disparity issue in SCT. However, a recent registry study showed increased incidence GvHD and inferior outcomes in patients receiving haploidentical SCT with PTCy, tacrolimus and mycophenolate mofetil for GvHD prevention as opposed to matched unrelated donor SCT with PTCy-based GvHD prevention. Seeking to improve the results of GvHD prevention in the setting of haploidentical SCT, we examined a combination of PTCy, abatacept and a short course of tacrolimus (CAST). Abatacept is a recombinant soluble fusion protein composed of the extracellular domain of cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) fused to the Fc region of IgG1. Abatacept blocks CD28-CD80I86 axis and prevents T-cell co-stimulation. In early studies, abatacept has shown promising results when added to methotrexate and tacrolimus in matched and mismatched donor SCT. We initiated a phase Ib-II clinical trial for patients with hematological malignancies undergoing haploidentical SCT. Patients received G-CSF mobilized peripheral blood grafts from related haploidentical donors. GvHD prevention consisted of PTCy 50mg/kg IV on day +3 and +4 with forced hydration, abatacept 10mg/kg IV on day +5, +14 and +28 and tacrolimus. Tacrolimus was started on day +5 at 0.02mg/kg/day by continuous IV and adjusted thereafter to maintain a trough level of 5-12ng/mL. Tacrolimus taper was planned to begin on day +60 and complete by day +90 in the absence of GvHD. All patients received standard supportive care including levofloxacin until neutrophil engraftment, posaconazole until day +75, acyclovir for 1 year and, if CMV positive by serology, letermovir until day +100. Pneumocystis Jiroveci prophylaxis was started after neutrophil engraftment and continued until 6 months post-transplant. G-CSF was administered routinely until neutrophil engraftment. Since September 2020, 19 patients were enrolled. Three patients are too early in their post-transplant course and were excluded from this analysis. Patients' characteristics are summarized in the table. All but 2 patients received cryopreserved products. Median times to ANC and platelet engraftment were 18.5 days (14-30) and 28.5 (16-61). All 16 patients achieved full whole blood donor chimerism by day +30. There was no secondary graft failure. With a median follow-up was 149.5 days (41-308) with 10 patients having >120 days and 8 >180 days of follow-up, 4 patients developed skin acute GvHD (all grade I). No patient developed grade II-IV acute GvHD. Two patients developed skin chronic GvHD (limited, both moderate). Both cases were diagnosed following COVID-19 vaccination. Fifteen patients completed tacrolimus taper by day +90. Two patients received systemic steroids, one for treatment of cGvHD. The remaining patients required no further immunosuppressive therapy beyond day +90. CMV activation rate was 25%. One patient had EBV reactivation and required preemptive therapy with 2 weekly rituximab doses. There were no cases of adenovirus, HHV-6 virus or BK virus reactivation. Four patients developed renal insufficiency (3 in the setting of acute sepsis and 1 with thrombotic microangiopathy, which resolved after tapering off tacrolimus. One patient with adult T-cell leukemia/lymphoma relapsed and died. All other patients are alive and well. In summary, our preliminary results suggest that CAST with shortened course of tacrolimus is feasible and seems to offer very promising outcomes with low rates of acute GvHD. The study is accruing actively and the results of a larger cohort with longer follow-up will be presented at the meeting. If confirmed, by improving the outcomes of haploidentical SCT, this regimen may further address a health care disparity issue, offering almost every patient in need of allogeneic SCT an alternative donor op ion with equal outcomes. [Formula presented] Disclosures: Al-Homsi: Daichii Sanyko: Consultancy;Celyad: Other: Advisory Board. Abdul-Hay: Abbvie: Consultancy;Servier: Other: Advisory Board, Speakers Bureau;Jazz: Other: Advisory Board, Speakers Bureau;Takeda: Speakers Bureau;Amgen: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Abatacept - off label use as GvHD prevention Cyclophosphamide - off label use as GvHD prevention

Cryopreservation of Unrelated Hematopoietic Stem Cells from a Blood and Marrow Donor Bank During the COVID-19 Pandemic: A Nationwide Survey by the Japan Marrow Donor Program.

During the COVID-19 pandemic, donor hematopoietic stem cell grafts are frequently cryopreserved to ensure the availability of graft before starting a conditioning regimen. However, the safety of cryopreservation has been controversial in unrelated hematopoietic stem cell transplantation (HSCT), especially for bone marrow (BM) grafts. In addition, in unrelated HSCT, the effect of the time from harvest to cryopreservation of donor grafts required for the transportation of donor graft has not been fully clarified. In this study, we retrospectively analyzed the first 112 patients with available data who underwent cryopreserved unrelated blood and marrow transplantation through the Japan Marrow Donor Program during the COVID-19 pandemic. There were 112 patients, including 83 who received BM grafts and 29 who received peripheral blood stem cell (PBSC) grafts. The median time from stem cell harvest to cryopreservation was 9.9 hours (range, 2.6 to 44.0 hours), and the median time from cryopreservation to infusion was 231.2 hours. The incidence of neutrophil engraftment at day 28 after HSCT was 91.1%, and among 109 patients (excluding 3 patients with early death), all but 1 patient achieved neutrophil engraftment within 60 days after HSCT. The time to neutrophil engraftment and time to platelet engraftment were shorter in PBSC transplantation compared with BM transplantation (BMT), but the differences were not statistically significant (P = .064 and .18). Multivariate analysis among BM recipients revealed that a higher number of frozen nucleated cells and the absence of HLA mismatch were associated with faster neutrophil engraftment. The time to neutrophil engraftment after unrelated cryopreserved BMT was not different from that after unrelated BMT without cryopreservation. Our findings suggest that unrelated donor BM and PBSC grafts can be safely cryopreserved even after transit from the harvest center to the transplantation center. In the current COVID-19 pandemic, cryopreservation can be considered as an option while balancing the risks and benefits of the procedure.