https://orcid.org/0000-0001-6783-2301
In this issue of Blood Advances, after almost 3 decades, Stefanski et al1 from the National Marrow Donor Program (NMDP) have demonstrated to the stem cell transplant and general hematology community that the use of filgrastim for stem cell mobilization is safe for volunteer hematopoietic stem cell donors. There was a period of >30 years in which bone marrow, obtained by direct harvesting, was the standard and sometimes the only source of hematopoietic stem cells. The introduction of mobilized blood-derived cells into allogeneic transplantation has resulted in them becoming the preferred and dominant source for transplantation and apheresis becoming the dominant method for stem cell collection, both for family member and unrelated transplants. It is notable that despite the known short-term risks associated with the operating room approach, the long-term safety of bone marrow collection has not been investigated before this current research being done.
This observational research was of a large number of participants compared with most undertaken in transplant studies. It involved 14 530 mobilized peripheral blood stem cell and 7123 bone marrow volunteer, unrelated donors. Its strength was near-universal and prospective data collection. The conclusions are clear and reassuring: myeloid malignancies are not more common in filgrastim-mobilized donors than in bone marrow donors and were very infrequent in both. The incidence of other hematologic and nonhematologic malignancies, autoimmune disease, or thrombosis were not different to that of age- and sex-matched individuals as reported by the Surveillance, Epidemiology, and End Results (SEER) program database.
Arguably, the introduction of filgrastim-mobilized autologous stem cells for autotransplantation in the early 1990s opened this form of therapy to many patients for whom it would otherwise have been not possible and saved many lives. This experience in autologous transplantation eventually led to investigation of the use of these cells in allogeneic donors. For all of this, we can thank the conclusions of the seminal study by Dührsen et al that demonstrated the mobilization of hematopoietic progenitor cells by filgrastim in patients with solid tumors.2 Filgrastim was a relatively new biologic at the time apheresis-based stem cell harvesting commenced, resulting in concern that a bone marrow stimulating cytokine might induce a variety of hematologic malignancies as well as other complications such as autoimmune diseases.3,4 This was of particular concern in volunteer donors. This notion was supported to some extent by in vitro studies suggesting genetic and epigenetic changes in cells induced by filgrastim.5
The methodology in this study by Stefanski used the extensive database developed prospectively by the NMDP for both blood cell and bone marrow donation under a series of investigational new drug trials. The donors were all unrelated volunteers, removing most of the impact of a family history of hematologic malignancy from the analysis, in contrast to the situation that might apply in a family member donor population. The same question in a population of predominantly related donors was addressed in a recent study from the European Group for Blood and Marrow Transplantation,6 which used a normal population as the comparator. It too failed to demonstrate an increase in the risk of malignancy in those donors. In this study of unrelated donors, the SEER database was interrogated as the comparator group for the relative risk of development of malignancy.
The use of allogeneic blood-derived, growth-factor mobilized stem cells, particularly from nonfamily member donors, was based on important early work that demonstrated feasibility as well as optimal regimens for cell collection.7 Currently, mobilized stem cells are by far the commonest source of allogeneic products for transplantation globally, although there are some regional variations.8
The findings of this study should reassure prospective donors that their donation does not come with a significant risk of long-term complications. In the future, it is probable that an increasing number of donors will receive other and newer mobilizing agents such as the chemokine (C-X-C motif) receptor 4 antagonist, plerixafor.9 Ongoing data collection by international registries will be essential to identify any safety signals that might emerge with these new agents. The World Marrow Donor Association has an existing reporting mechanism for any adverse events that may emerge with current and new agents.10 This system is managed by a supervisory committee that can produce global alerts if any unexpected and serious observation in donors is made.
Conflict-of-interest disclosure: J.S. reports advisory committee, consultancy, speaker bureau fees, and travel assistance from Alexion Pharmaceuticals and Sobi Pharmaceuticals; advisory committee with Novartis; and consultancy fees from ADARx Pharmaceuticals, Kira Pharmaceuticals, Samsung Bioepis, and Novartis.
