¹Department of Blood and Marrow Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

²Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence to: Dr P Anderlini, Department of Blood and Marrow Transplantation, Room FC5. 3062, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 423, Houston, TX 77030-4095, USA

Data on the long-term safety of filgrastim administration in peripheral blood progenitor cell (PBPC) donors are scarce. The main theoretical risk is believed to be the possible development of leukemia. We conducted a survey of filgrastim-treated related donors to determine the incidence of leukemia after PBPC donation. Of the 343 PBPC donors eligible for inclusion in the survey, 281 (82%) were interviewed by telephone between December 1998 and February 2000. The mean age at donation was 44 years. The median time elapsed after PBPC donation was 39 months, and in 278 (99%) of the interviewed donors it was at least 1 year. At the time of the interview none of the donors had been diagnosed with acute or chronic leukemia. Although the sample size is small and the follow-up duration is limited, these data suggest that exposure to filgrastim is not associated with any notable risk of leukemia development in PBPC donors.

Bone Marrow Transplantation (2002) 30, 661-663. doi:10.1038/sj.bmt.1703693

filgrastim; rhG-CSF; allogeneic peripheral blood progenitor cell transplantation; normal donors; leukapheresis

With the steadily increasing use of recombinant human granulocyte colony-stimulating factor (rhG-CSF; filgrastim) in normal donors of peripheral blood progenitor cells (PBPCs), the issue of possible long-term adverse events related to its administration takes on a new urgency and relevance.^1,2 Initially, rhG-CSF was employed almost exclusively in related (ordinarily sibling) donors, but now it is also administered to unrelated donors to mobilize (and collect) PBPCs.³ G-CSF receptors are present almost exclusively in hematopoietic cells of myeloid lineage;⁴ therefore the main theoretical risk associated with exposure to filgrastim is that it could lead to the late development of leukemia, particularly acute or chronic myeloid leukemia. Data on the long-term follow-up of normal PBPC donors are scarce. Published reports have involved only small numbers of PBPC or granulocyte donors who were followed-up for relatively short periods of time.^5,6,7,8 We present the results of a long-term follow-up study conducted as a telephone survey of filgrastim-treated donors whose PBPCs were harvested at our institution.

Materials and methods

A survey was conducted of all PBPC donors enrolled and registered in the PBPC collection protocol at our institution between 1994 and 1998. This time period was selected to ensure adequate long-term follow-up. The study protocol was approved by our institutional review board and the participants provided informed consent. In total, 396 PBPC donors were included in the database. They underwent filgrastim administration for 3-5 days in most cases, followed by PBPC apheresis. The filgrastim dose was ordinarily 6 g/kg subcutaneously twice daily. The donors were interviewed by telephone between December 1998 and February 2000. The questions included in the interview inquired about the current health status of the PBPC donor and whether he/she had been diagnosed with leukemia (as well as other hematological conditions). They also included questions about the effect of the donation experience on the future willingness to donate for a family member, for a non-family member or for a marrow or stem cell bank. PBPC donors were asked to rate their satisfaction with their overall experience as a donor.

Results

Fifty-three of the donors in the database were excluded from the survey (49 were not living in the United States, three had blank records or no donor name was available, and one person had not actually donated). Of the remaining 343 donors, 281 (82%) were interviewed. Sixty-two donors were not interviewed because no current contact information was available (n = 36), they declined to participate (n = 10), no response was obtained after multiple contact attempts (n = 14), or they had expired (n = 2: one suicide, one cerebrovascular accident, both seemingly unrelated to the donation). The first donor expired 18 months after donation, and the second donor (a 54-year-old woman) has been reported previously.⁹

The mean age at the time of donation was 44 years (range 5-77 years), 132 (47%) were men and 149 (53%) were women. Two hundred and thirteen (76%) were Caucasian, 48 (17%) were Hispanic, 14 (5%) were Black, and six (2%) were of other ethnic origins. The donor was usually the sibling of the recipient (n = 270; 96%), with 11 (4%) being some other blood relative. The median time elapsed after the PBPC donation was 39 months (range 7-80 months), and in 278 (99%) it was at least 1 year. Six donors had donated stem cells at other institutions. At the time of the interview none of the donors had been diagnosed with acute or chronic leukemia.

Among the interviewed donors, 244 (87%) expressed a future willingness to donate to a family member, although only 135 (48%) and 124 (44%) were willing to donate to a non-family member or a stem cell bank, respectively. Fifty-nine (21%) and 76 (27%) donors expressed their unwillingness to donate to a non-family member or a stem cell bank, respectively, with the remainder willing to undertake or at least consider such donation. Eighty % (n = 225) of the PBPC donors rated their donation experience as 'satisfying'. Of these, 143 (51%) rated it as 'highly satisfying'. Of the remainder, 48 (17%) rated it as 'somewhat satisfying' and only 3% (n = 8) considered it as 'quite dissatisfying'.

There was no difference in the participants' willingness to donate stem cells to a bank by ethnicity. However, as expected, donors who did not have a positive experience (satisfaction with the procedure) as donors were less likely to be willing to donate to a bank than the satisfied ones (33 vs 44%; P = 0.5).

Discussion

The challenging logistical and statistical issues involved in monitoring the long-term risk for the development of acute leukemia in PBPC donors have been reviewed in detail elsewhere.¹⁰ The development of acute leukemia in the general United States population is rare, with a reported incidence of five cases per 100 000 persons per year. To detect a substantial (and improbable) 10-fold increase in this rate, it is estimated that no fewer than 2000 PBPC donors would need to be followed-up for 10 years or longer.¹⁰ Published studies fall far short of this target. Cavallaro et al⁵ reported 95 donors who had been contacted a median of 43 months after PBPC or granulocyte donations, and found no reported cases of leukemia. Stroncek et al⁶ evaluated 19 PBPC donors 1 year after donation, Storek et al⁷ described nine healthy PBPC donors 1 year after PBPC collection and Sakamaki et al⁸ reassessed three healthy volunteers 5 years after rhG-CSF exposure. None of these authors reported any cases of leukemia. Unfortunately, it is unclear whether the long-term monitoring of thousands of PBPC donors would be feasible or realistic, but this remains the only appropriate way to address this problem. To complicate things further, it is also possible that these donors, in view of their HLA similarities with patients with leukemia, may have a higher risk of developing leukemia than the general population.¹¹ Nevertheless, it seems advisable and prudent that individual institutions, transplant centers and registries make every reasonable effort to maintain long-term surveillance of their PBPC donors.

Donors were asked whether they had been diagnosed with leukemia. Therefore, all that this study can attest to is that none of these donors had seemingly been diagnosed with leukemia at the time of the interview. Whether a laboratory evaluation in the form of a hematology survey (not a planned part of this study for logistical and cost considerations) may have revealed one or more asymptomatic leukemia cases remains to be determined.

In conclusion, although the sample size is small and the length of follow-up is limited, this survey suggests that brief exposure (3-5 days) to filgrastim during the PBPC donation process is not associated with any notable long-term (3-4 years) risk for the development of leukemia. These data should provide some reassurance to donors. It is also reassuring to note that most PBPC donors retained their willingness to donate to a family member after their donation experience, and that the vast majority rated their donation experience as satisfying or highly satisfying.

Acknowledgements

We are indebted to Ms Margie Torres and Ms Muriel Giese for her secretarial assistance. We are also indebted to Mrs Karen F Phillips for her review of the manuscript.

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