Impact of cryopreservation and transit times of allogeneic grafts on hematopoietic and immune reconstitution

Abstract

We sought to evaluate the impact of cryopreservation of unrelated donor peripheral blood stem cell (PBSC) grafts on engraftment, chimerism, and immune reconstitution in the context of the Covid-19 pandemic. We reviewed stem cell product characteristics and clinical outcomes in 101 patients receiving cryopreserved PBSCs from unrelated donors (URD) between January 1, 2019, and December 31, 2020, compared with 203 patients receiving fresh URD PBSCs. We observed no differences in 6-month overall survival, progression free survival, or non-relapse mortality. Patients receiving cryopreserved PBSCs had delayed platelet engraftment and impaired reconstitution of white blood cells and T cell subsets at Day 30. Thirty-four percent of patients receiving cryopreserved grafts had CD3 chimerism <50% at Day 30 after transplantation, compared with 14% of patients receiving fresh PBSCs (p=0.0002). At day 100, this difference persisted (CD3+ chimerism <50%: 17% of cryopreserved cohort vs 6% of fresh cohort, p=0.016). Additionally, greater product age at infusion is associated with an increase in graft failure, independent of cryopreservation. Receipt of grafts >48 hours old at time of cryopreservation or infusion significantly increased the risk of graft failure (sHR =4.57 (95% CI 1.71-12.3), p=0.0025). Our data indicate that cryopreservation is associated with similar overall short-term clinical outcomes compared to fresh PBSC. However, patients must be monitored closely for increased risk of other potentially adverse outcomes including graft failure and poor immune recovery, particularly for grafts with older overall age at infusion. Longer term follow-up is needed to determine impact on relapse and survival.

Impact of Cryopreservation and Freeze-Thawing on Therapeutic Properties of Mesenchymal Stromal/Stem Cells and Other Common Cellular Therapeutics

“…Although HSPC grafts can be used fresh, modern routines often rely on cryobanking of BM, CB and PB grafts [ 50 – 54 ]. Particularly, CB and PB grafts are often stored cryobanked until clinical use [ 51 , 55 – 57 ]. Experience during the COVID-19 pandemic suggests that even in the well-established HSCT setting, cryopreservation and increased transit times can detrimentally affect immune reconstitution [ 57 , 58 ].…”

Zelltherapie in den Zeiten von SARS-CoV-2

“…Dies nicht vollumfänglich bestätigende Daten berichten hingegen US-Kollegen, deren Arbeiten zu diesem Thema zwar etwas später entstanden, aber bezüglich der Patientenergebnisse sehr viel detaillierter sind. Analysen vorwiegend mit myeloablativen Protokollen Transplantierter zeigen gegenüber in der prä-COVID-Ära mit frischen Transplantaten versorg-ten Patienten bei Empfängern kryokonservierter Transplantate leicht verzögertes myeloides und T-Zell Engraftment sowie verlängerten gemischten Chimärismus, allerdings wie bei uns keinerlei Effekt auf Gesamt-oder Progress-freies Überleben, Rezidivwahrscheinlichkeit oder Nicht-Rückfalls-Mortalität [24]. Überraschend war die signifikant erhöhte Wahrscheinlichkeit von Empfängern kryokonservierter Transplantate, eine schwere GvHD zu erleiden [24].…”

“…Analysen vorwiegend mit myeloablativen Protokollen Transplantierter zeigen gegenüber in der prä-COVID-Ära mit frischen Transplantaten versorg-ten Patienten bei Empfängern kryokonservierter Transplantate leicht verzögertes myeloides und T-Zell Engraftment sowie verlängerten gemischten Chimärismus, allerdings wie bei uns keinerlei Effekt auf Gesamt-oder Progress-freies Überleben, Rezidivwahrscheinlichkeit oder Nicht-Rückfalls-Mortalität [24]. Überraschend war die signifikant erhöhte Wahrscheinlichkeit von Empfängern kryokonservierter Transplantate, eine schwere GvHD zu erleiden [24]. Im Kontext der Post-transplant-Cyclophosphamid-unterstützten (PtCy-unterstützten) unmanipulierten haploidenten Transplantation wurden keine klinisch relevanten Veränderungen der Transplantations-Erfolge durch Einführung der generellen Kryokonservierung berichtet [25].…”

Impact of Cryopreservation of Peripheral Blood Stem Cells (PBSC) in Transplantation from Matched Unrelated Donor (MUD)

“…Prior to the COVID-19 pandemic, donor grafts in allogeneic hematopoietic stem cell transplantation (allo-HSCT) were usually administered fresh [ 1 , 2 , 3 ]. The ongoing COVID-19 pandemic caused significant logistical difficulties in the management of allo-HSCT from unrelated donors.…”

“…Goods and people transport limitations as well as the risk of SARS-CoV-2 community-acquired infection of donors during stem cell mobilization and collection prompted the main international scientific societies and regulatory authorities to recommend the cryopreservation of stem cells to ensure the safety of transplant procedures [ 4 , 5 ]. However, while the experience related to the cryopreservation of HSC is well established in the autologous and cord blood source [ 6 , 7 , 8 ], in the literature there are a few controversial data regarding allogeneic grafts, especially in the unrelated donors setting [ 1 , 2 , 3 , 9 , 10 , 11 , 12 , 13 , 14 ]. An important aspect to consider, especially in the MUD setting, is the time from collection to cryopreservation and infusion.…”