Ethical and policy lessons to be learned from a family with inherited bone marrow failure^†

The case report by Denny et al. 2008 highlights the fact that good ethical analysis must begin with an understanding of the medical facts. The case also raises important ethical and policy considerations for the hematology, genetics, and pediatric communities.

The case involves a 27-year-old woman with aplastic anemia due to clinically diagnosed dyskeratosis congenita (DC) in a family in which the condition is inherited as an autosomal dominant condition [de la Fuente and Dokal, 2007]. The proband was considering a hematopoietic stem cell transplant from one of her four siblings, all of whom were clinically asymptomatic at the time. Three siblings were HLA-compatible, but the hematologist told the family that the proband's 13-year-old brother would be an “ideal” stem cell donor for his sister [Denny et al., 2008]. The medical question that arises is whether the 13-year-old should have been singled out as truly “ideal,” because the fact that he was asymptomatic at 13 years did not mean that he was not genetically at risk for developing symptoms in young adulthood, and therefore not an “ideal” donor.

Denny et al. examine the genetic work-up from a family-focused perspective. They note that 23 relatives including the proband's 13-year-old brother volunteered to participate in a natural history study at the National Cancer Institute. At that time, the 13-year-old explicitly requested not to learn the results of testing from known germline mutations associated with DC [Denny et al., 2008]. However, approximately 11 months later, when the research team learned that the 13-year-old was planning to serve as a stem cell donor, the research team expressed concern that transplants from donors with unrecognized non-penetrant genetic diseases may be less successful [Denny et al., 2008]. Although no germline mutation had been found in the family, the 13-year-old had short telomeres which are not pathognomic but highly suggestive of the diagnosis of DC [Vulliamy et al., 2001; Alter et al., 2007]. The short telomeres may also make him a less ideal transplant donor as short telomeres are associated with a lower likelihood of engraftment. [Akiyama et al., 2000; Calado and Young, 2008].

The analysis by Denny et al. is insightful and shows how genetics is forcing us to reconsider our traditional medical ethics paradigm which focuses on the rights of individuals in isolation from the concerns of their family (or in other cases, their ethnic community). This need for a greater communal focus, however, is not unique to genetics [Gostin and Hodge, 1999; Ross, 2001]. For example, public health challenges like HIV also force medical ethicists to take on a more communal focus and to consider the implications of an individual's decisions for known and unknown third-parties [Ross, 2001].

The case, however, must also be examined from the perspective of evolving medical knowledge and the decision by the hematologists to “pre-select” or single out one sibling as the “ideal stem cell donor.” Hematopoietic stem cell transplantation has evolved a great deal in the past half century. While HLA-matching is still the primary consideration for donor selection, many other factors including age and gender have come play a greater role than previously realized [Loren et al., 2006; Stern et al., 2006], as do minor-histocompatibility factors [Perez-Garcia et al., 2005; Spierings and Goulmy, 2007], genetic polymorphisms [Dickinson and Middleton, 2005] and viral exposures [Ljungman, 2007]. The pre-selection of one sibling fails to acknowledge the evolving nature of (1) genetics: by the late 1990s, DC was understood to be a disease associated with telomere shortening [Vulliamy et al., 2001]; (2) telomere biology: in the past decade, there has been growing understanding that donors with shorter telomere lengths (whether due to age or medical condition) are less ideal transplant donors [Akiyama et al., 2000; Calado and Young, 2008]; and (3) stem cell transplantation for DC: the data to-date show that transplantation of patients with DC is often associated with serious if not fatal complications [Rocha et al., 1998; de la Fuente and Dokal, 2007; Calado and Young, 2008; Savage and Alter, 2008]. While changes in the conditioning regimen are encouraging, these negative results are important given data to show the psychological impact of a failed transplant on donors [Shama, 1998; Heiney et al., 2002; MacLeod et al., 2003]. Pre-selection also fails to acknowledge that the health status of the siblings is dynamic. First, DC may not present until adulthood so that one had to be concerned that the 13-year-old who is asymptomatic at the time of HLA-testing could still be “at risk” [Savage and Alter, 2008]. One also had to be concerned that any of the siblings could become infected with any number of viral infections that would have precluded donation (e.g., HIV) or at least made the potential donor less desirable (e.g., CMV) between the time of initial work-up to transplant.) Having been “pre-selected,” the exclusion of the potential donor now would imply new health issues, the disclosure of which would conflict with his right to privacy.

The decision to pre-select is made more disturbing because the selected sibling was a minor. Currently stem cell donation by minors is unregulated. Although there are numerous statements that discuss the role of minors serving as solid organ donors [Live Organ Donor Consensus Group, 2000; Delmonico and Council of the Transplantation Society, 2005; Ross et al., 2008] no such statement exists for hematopoietic stem cell transplantation. Likewise, although all living solid organ donors are required to have a donor advocate who is independent of the team caring for the transplant recipient [Department of Health and Human Services, 2007], no such requirement exists in stem cell transplantation. Although one could argue that the risks of donation are much lower for the stem cell donor, risks exist and should be articulated as part of the decision making, particularly when the donor may be a minor.

The medical risks of hematopoietic stem cell transplantation depend, in part, on how the stem cells are collected. The major risk of bone marrow collection is anesthesia, but other serious complications include nerve, bone, or tissue injury [Pulsipher et al., 2006]. Other risks include the need for transfusions, wound infection, and pain at the site of marrow aspiration. Peripheral blood stem cell (PBSC) collection is also possible. The major risk of PBSC is the placement of two large catheters and the use of granulocyte-colony stimulating factor (G-CSF) to increase the number of circulating stem cells. Most G-CSF effects are thought to be transient and self-limited, but long-term data are lacking [Pulsipher et al., 2006]. Short-term effects include fatigue, low back pain, sleeping problems, light-headedness and difficulty walking [Kennedy et al., 2003].

The psychological risks of serving as a stem cell donor may be greater than the physical risks. Data show that many sibling donors experience sleep difficulties, behavioral problems, and problems in school although it is hard to tease out the effect of being a donor and of having a seriously ill sibling [Packman et al., 1997a,b; Shama, 1998; Wiener et al., 2007, 2008]. Not surprising, siblings of recipients who underwent unsuccessful transplants reported greater negative impact and feelings of guilt than those of recipients whose transplants were successful [Shama, 1998; MacLeod et al. 2003; Wiener et al., 2007]. Given the historically poor results with stem cell transplantation in patients with DC, these concerns take on greater significance.

One could take a very conservative position and argue that the 13-year-old minor should not have been tested for HLA compatibility because of his youth. This position is strengthened by the fact that his sister's illness was not of extreme medical acuity that required the rapid identification and preparation of a stem cell donor. Had his sister suffered from a condition that required a more urgent stem cell transplant, delay in identifying a histocompatible donor could have harmed her chances of treatment success, such that the decision to test all siblings simultaneously would be justified. But given the more indolent nature of aplastic anemia and alternate short-term therapeutic options [de la Fuente and Dokal, 2007; Calado and Young, 2008], one could have argued to counsel the family to try to find a stem cell donor from amongst the older siblings.

The conservative position is weakened by both pragmatic and ethical arguments that support the participation of minors as stem cell donors, with appropriate safeguards [Pentz et al., 2004]. Pragmatically, one would not want to exclude all minor donors to the extent that medical matching is crucial for successful stem cell transplantation [Dickinson and Middleton, 2005; Perez-Garcia et al., 2005; Loren et al., 2006; Stern et al., 2006; Spierings and Goulmy, 2007]. Ethically, one would not want to exclude all minor donors to the extent that one believes that there can be moral obligations that exist within families, even if not accrued voluntarily [Glannon and Ross, 2002; Pentz et al., 2008]. However, the participation of minors does require a moral commitment to ensure that their interests are represented. In the solid organ transplant world, this is being achieved by an independent donor advocate or donor advocate team [Bramstedt, 2007; Ross et al., 2008], and a similar position would be valuable for stem cell transplants as well.

Denny et al. 2008] should be commended for how they addressed the issue of reporting telomere test results. The research team invited the entire family back to explore newly discovered medical understanding of telomere length and to explain how this might impact their desirability as a donor and also their risk of being “at risk.” Unfortunately, the re-contact with new information was flawed because the one sibling had already been pre-selected. In this case, the 13-year-old may no longer have felt that he had a choice but to learn his diagnosis. To say he did not want to know the telomere test results would force himself to be disqualified from serving as a stem cell donor, and could be understood, not as a desire “not to know his genetic risks,” but as a desire not to serve as a donor. Thus, although each family member was offered the opportunity to learn or not to learn the results of telomere testing, the 13-year-old was placed in an untenable position. As the authors note, “He never discussed his earlier decision to opt out of genetic testing” [Denny et al., 2008].

How could this have been handled better? There was no need to pre-select a donor. The fact that the proband had three HLA compatible siblings meant that all three could have undergone further work-up at the time that the proband elected to undergo transplantation, particularly in a family where asymptomatic relatives may have developed some degree of hematologic or physical symptoms during the 1 year period between testing and transplantation preparation. Had pre-selection not occurred, a donor advocate could have met with each HLA compatible sibling to determine (1) how willing they were to undergo additional testing that would strengthen or weaken their donor desirability; and (2) what information they would want to learn from the additional testing, including telomere length. Then, the 13-year-old could have maintained his decision not to know his genetic status. It would have been decided that another sibling was the “ideal” donor and the basis for his non-selection would have been unspecified.

Membership in families matters. It matters for the beneficial emotional interdependence that is often expressed within the family, for the genetic and medical health factors that families share, and for the ethical obligations that ensue from such membership. While the hematology team focused on their primary patient, the potential recipient, and the ethics consult focused on the needs and interests of the potential recipient and her potential sibling donors interdependently, a stem cell donor advocate would ensure that the rights, interests and needs of the potential stem cell transplant donors are independently recognized and given full ethical consideration both in the research and clinical settings. This is most critical when the donors are minors who are less likely to understand that the medical work-up required for stem cell donation may have serious unintended consequences, including the disclosure of unwanted information.