key: cord-0705621-3ycjk5f8
authors: Allan, David S.
title: A Timely CIBMTR Analysis of How Cryopreservation Impacts Allogeneic Hematopoietic Cell Transplantation to Apply in the COVID Era
date: 2021-06-15
journal: Transplant Cell Ther
DOI: 10.1016/j.jtct.2021.05.009
sha: c2ae022f61343a9c3528e0c0f5af52392029214e
doc_id: 705621
cord_uid: 3ycjk5f8

nan

At several critical stages of the COVID-19 pandemic, transplant centres have embraced the practice of universal cryopreservation of unrelated allogeneic stem cell products. Cryopreservation of products prior to initiating the conditioning regimen provides assurance that the product is available before committing patients to high dose chemotherapy and immune suppression. Indeed, it remains astounding that collecting cells from allogeneic donors, whether related or unrelated, and whether from down the road or across the world, remains feasible at all given issues with stay-at-home orders, international and regional travel restrictions, issues with access to hospitals, donor fears of interfacing with health care systems, and transplant centres facing the dilemma of starting patients on treatment when ICUs, blood banks and hospital services are stretched thin or even overwhelmed. The extent to which cryopreservation compromises graft quality and patient outcomes during the pandemic, however, remains uncertain. Even if clinical outcomes are compromised marginally, are patients better off to proceed to transplant under these conditions rather than delay transplant? A recent report from the Memorial Sloan Kettering Centre in New York suggests delaying HCT or CAR-T therapy lead to some patients relapsing before they could undergo cell therapy 1 . Naturally, balancing the risks and benefits of cryopreservation during COVID-19 has resurfaced questions about the impact it may have on transplant outcomes.

Prior studies of cryopreservation have been limited by small numbers and bias regarding the reason for cryopreservation, although collectively, appear to show no significant impact on time to initial engraftment, GVHD, relapse, or survival 2 . In the report by Hsu et al in this issue of TCT 3 , the authors analyzed the impact of cryopreservation on 1883 patients who received cryopreserved marrow, related PBSC or unrelated PBSCs with 5514 matched controls. This is by far the largest study addressing this issue and a clear strength of this analysis using data from the CIMBTR registry is their ability to identify large well-matched control groups for comparison. It should be noted, however, that the transplants included in this analysis were from 2013-2018 and while recent and reflective of current practice, did not represent the universal cryopreservation approach adopted during COVID-19. Prior to this pandemic, cryopreservation was typically considered for patient reasons such as disease persistence or progression that requires additional treatment after the arrangements for collection have been finalized and where rescheduling the collection is not feasible, or in cases where additional time is needed to treat an infection or to allow greater recovery for deconditioned patients. This is a significant difference from the situation observed during COVID-19 where patients were typically stable and ready to proceed, and cryopreservation was done to overcome concerns that the product would be collected and arrive on time. It is also possible, that cryopreservation in the related donor setting is used more often for logistical reasons, rather than patient-specific issues. This has been described by some larger programs that struggle to optimize scheduling and meet the demand for transplant volumes by cryopreserving related grafts 4 . The same strategy has not been widely supported or adopted for unrelated stem cell grafts and registries even issued a notice of concern regarding the perception of excessive cryopreservation of unrelated donor products during a lull in the current pandemic due to concerns cryopreserved grafts may never be infused. This ethical dilemma of exposing donors to unnecessary risk when products are not infused is a chief argument against universal cryopreservation. Whether cryopreservation negatively impacts transplant outcomes has always been less clear and has contributed less to decisions regarding approval of cryopreservation requests by international registries. In a recent analysis of the Stem Cell Registry at Canadian Blood Services, approximately 7% of cryopreserved grafts were never infused. Balancing this "waste" against the benefits of facilitating more transplants for more patients remains unresolved and requires further exploration and analysis.

In the study by Hsu et al, they addressed outcomes based on donor graft type. Concerning marrow grafts, multivariate analysis revealed no impact of cryopreservation on engraftment, relapse, NRM or overall survival. For related PBSC grafts, decreased rates of platelet recovery at 100 days (HR 0.74) and increased GVHD (HR 1.27 for grades II À IV acute GVHD) were observed. In cases of unrelated PBSC cryopreservation, lower rates of engraftment of neutrophils by day 28 and platelet Transplantation and Cellular Therapy journal homepage: www.tctjournal.org engraftment by day 100, greater NRM (HR 1.4) and relapse (HR 1.32) and reduced overall survival (HR 1.38) were observed. While travel time was considered for a subset of cryopreserved grafts collected from domestic centres, the impact of longer transit times for products collected at international sites was not available and would be interesting to address. When considering factors specific to the pandemic, more circuitous routing of flights could prolong transit times further and centres with less experience performing cryopreservation may have impacted the viability of products after thawing. An updated analysis focused on the pandemic era will be interesting and insightful. While data was not available for all patients, a change in patient condition was the most common reported reason for cryopreservation in the unrelated setting in this report. This is quite distinct from the pandemic situation. While the study did not include an analysis of graft composition, others have demonstrated a reduction in regulatory T cell activity that may explain greater GVHD and more relapses as these regulatory cells may favor graft-versus-leukemia effects over GVHD. Reduced numbers of total nucleated cells, even if CD34+ cell numbers are not reduced, may diminish availability of chaperone cells that can impact engraftment. With their observation of reduced OS and greater relapse, it is possible that competitiveness of cryopreserved HSCs to repopulate the marrow is reduced, leading to greater persistence of disease-causing cells compounded by delayed graft-versus-leukemia effects.

As the pandemic recedes, transplant centres are likely to revert to using fresh products, in part encouraged by unrelated donor registries keen to protect the interests of donors, but also by transplant centres acting in the best interest of patients, as long as the cells can be collected and transported reliably and on schedule. With the results of Hsu et al, there is further justification to return to the practice of using fresh PBSC products, reserving cryopreservation for special cases where a compromise in graft quality is offset by the need to delay the transplant.

Cellular therapy during COVID-19: Lessons learned and preparing for subsequent waves

Cryopreservation of adult unrelated donor products in hematopoietic cell transplantation: the OneMatch experience and systematic review of the literature

The effect of donor graft cryopreservation on allogeneic hematopoietic cell transplant outcomes: A CIBMTR analysis. Implications during the COVID-19 pandemic

Similar outcomes of cryopreserved allogeneic peripheral stem cell transplants (PBSCT) compared to fresh allografts