Donors, donors, and more donors

In this issue of Blood, Hölig and colleagues report on their 12-year experience with healthy unrelated donors. Their data outline the challenges involved in safeguarding donor safety and the need for ongoing surveillance.

The safety of healthy peripheral blood stem cell (PBSC) donors receiving recombinant human granulocyte colony-stimulating factor (rhG-CSF) is a topic that has received considerable attention in recent literature.^1-3  The short-term adverse events related to both mobilization and collection as well as the problem of long-term safety monitoring have been discussed extensively, although the latter issue is far more complex and logistically more challenging for investigators.

Hölig and colleagues⁴  provide a major contribution to this debate. They managed an impressive number of donors (3928) over a 12-year period, a noteworthy (and quite possibly unique) accomplishment for a single center. As it has been said, quantity has a quality all of its own. Their data on short-term donor outcome are, indeed, remarkable. One leukapheresis was adequate to collect the target CD34⁺ cell dose in 78% of the donors. Only 1.1% of them experienced serious complaints requiring hospitalization, and there were no cases of splenic rupture. Their “mobilization failure” rate was as low as 0.45%, and a central venous access was needed in only 0.6% of cases. That being said, it should be acknowledged that these are selected, healthy, presumably very committed young volunteer donors (median age, 34 years) being followed at a highly skilled referral center. Therefore, these results may not necessarily be reproducible in other settings, particularly those involving older related donors.

As impressive as these figures may be, the contribution from Hölig and colleagues is even more valuable when it comes to long-term follow-up and their ability to monitor their cohort of 3928 unrelated volunteers for a period of up to 5 years (see figure). Most donors reported good or very good general health. With a follow-up including 8234 donor-years, the fact that the incidence of myeloid malignancies was not significantly different from the one expected from an age-adjusted population is undoubtedly reassuring. The finding of a higher incidence of Hodgkin lymphoma defies an immediate explanation. It is provocative and deserves to be explored further. Similar data have recently been reported by the National Marrow Donor Program (NMDP).⁵  Among 4015 donors who have passed the first anniversary of their PBSC donation, the NMDP has accumulated 9785 years of follow-up (range, 1-9 years, with 897 donors ≥ 4 years). The incidence of cancer in this group was consistent with the age-adjusted US incidence of cancer in the normal adult population, with no reports of leukemia or lymphoma. To put all of this in perspective, it is appropriate to draw from the original analysis from Hasenclever and Sextro.⁶  The annual incidence of acute leukemia in the United States is estimated to be 5/100 000 per year, yielding a cumulative incidence of 0.05% cases at 10 years. Assuming a 10-fold increase in leukemia risk in these donors, which is clearly a pessimistic scenario, more than 2000 donors would need to be followed for longer than 10 years. It could be argued that the use of a normal adult control population does not take into account the fact that these donors are HLA-identical to patients with hematologic malignancies, and therefore ignores any possible genetic or familial predisposition to leukemia development. It is difficult to see, however, how this potential confounding factor can be bypassed in the real world.

Although this study is indeed reassuring, there is an ongoing need for surveillance and caution. A flurry of reports on possible effects of rhG-CSF on chromosomal integrity and gene expression have been published in recent years and have been recently reviewed.⁷  The effects described on gene expression were self-limiting and transient. In addition, these studies are small, have been subject to criticism, have not been widely replicated so far, and should be viewed as inconclusive. Still, safeguarding donor safety is such a high priority that one can only welcome efforts to evaluate these leads. The United Kingdom Donor Registries will have a study to screen normal donors treated with recombinant human granulocyte colony-stimulating factor for long-term genetic damage using interphase fluorescence in situ hybridization and array comparative genomic hybridization analysis.¹  Marrow donors will be used as negative controls and patients with hematologic malignancies as positive controls. The NMDP and University of Minnesota are working on a similar study.¹