Matched Marrow,Sibling Shadow: The Epidemiology,Experience,and Ethics of Sibling Donors of Stem Cells

Evidence for Sibling Donation

HLA-matched siblings have historically been considered the optimal donors for medical, biological, economic, and logistical reasons. ³ Human leukocyte antigen (HLA) match is recognized as a most important donor-related determinant of a patient's outcome after allogeneic bone marrow transplant. ⁴ When comparing complications, relapse, and survival among recipients of HLA-matched sibling donation versus HLA-matched unrelated donation, sibling donors are more likely to result in superior results in terms of engraftment, graft-versus-host disease, infection rate, treatment related mortality, and survival.^5–7 To qualify as a donor, the adolescent or young adult sibling ideally has a healthy heart, lung, liver, and kidney function as confirmed on medical tests and comprehensive physical exams; is free from active infectious diseases; and is immunocompatible with the recipient sibling. To date, sibling donors have been recruited in 39–48% of all childhood bone marrow transplants. ⁸ An interesting shift is the recognition that with current transplantation techniques, haploidentical transplantations are an increasingly viable option for patients with high-risk leukemia that may offer similar overall survival to recipients of HLA-matched donor transplantation options. ⁹ Haploidentical transplant involves use of a mismatched related donor, often a parent in pediatric transplantation. With recent advances in cord blood and haploidentical options, “now everyone has a donor” ¹⁰ regardless of whether everyone has a matched sibling. ¹¹

Sibling Experience

The sibling experience in serving as a hematopoietic progenitor cell donor varies based on whether the sibling is donating cells via bone marrow versus peripheral blood collection. Collection of hematopoietic progenitor cells for both bone marrow and peripheral blood procedures is generally safe; only one serious adverse event (pneumothorax after central line placement) was reported in a study of more than 450 pediatric-age stem cell sibling donors in a multicenter, prospective trial. ¹²

Stem cell collection often occurs after Granulocyte-Colony Stimulating Factor (G-CSF) stimulation. This preparatory medication is usually given to the donor in the form of a subcutaneous daily injection to stimulate the bone marrow to release essential white blood cells and stem cells into the donor's blood stream. Adverse events or side effects of G-CSF priming in healthy sibling stem cell donors may include bone pain, muscle aches, headache, and nausea. ¹³

For sibling donors providing stem cells by apheresis collection, the median duration of the procedure is generally 4 h, although more than one apheresis session may be required. The need for central access for apheresis is less likely in adolescent-age siblings compared with younger siblings. ¹⁴ Other consequences of sibling donor leukapheresis may include temporary symptomatic hypocalcemia, exposure to blood products during priming of the apheresis machine, low platelets, difficulty with clotting, racing heart, or low blood pressure.^13,15

In the setting of bone marrow collection, 50% of sibling donors experience pain requiring analgesia, 9% experience temporary lumbar stiffness, and 7% experience sore throat from intubation. ¹² If there is a significant size difference between the sibling donor and the recipient, the sibling donor may require a blood transfusion after the procedure in rare circumstances. ¹²

In a prospective, longitudinal study of unrelated, primarily adult hematopoietic stem cell donors, two thirds of donors reported that the donation was physically stressful, and 60% reported the donation as emotionally stressful (n=273 respondents) 48 h after collection. ¹⁶ While the donor experience of physical discomfort is notably temporal and relatively short-lived, ¹⁷ older adolescents siblings may be at risk of anxiety surrounding the procedure: one study found that 40% of sibling donors aged 18 years or older were “pretty nervous” or “extremely nervous” about the procedure, while only 22% of the donors younger than 18 years old reported being “pretty nervous” or “extremely nervous.” ¹⁸

Potential Psychological Benefits and Burdens of Sibling Donation

While unrelated adult donors often experience a universal sense of purpose and pride after donation (unrelated donors are often unaware of recipient morbidity or mortality post-transplant), sibling donors have been reported to experience a range of emotions, often influenced by the donation outcome. An investigation of 493 unrelated adult donors revealed the donor's perceived benefits of donation: feeling proud to have donated (94%), feeling like donation was a high point in their lives that made everything seem more meaningful (75%), feeling like a better person for having donated (71%). ¹⁹ Likewise, sibling donors of all ages have cited the positive effects of successful donation: enhanced family relationships through donating, increased feelings about self, decreased helplessness, and insight into their sibling's illness. ²⁰

Donor siblings face the double hit of not only being a sibling to a chronically ill child, but also facing the added responsibility of serving as a donor. Unlike unmatched donors who are often unaware of their transplant recipient's outcome, sibling donors may carry a sense of guilt when a complication such as graft-versus-host disease occurs secondary to the transplant or if their sibling does not survive. In a survey of sibling donors between the ages of 7 and 20 years (n=15 siblings, M_age=13.3 years), sibling donors of transplant recipients who had died reported greater negative impact and feelings of guilt following the donation and were less likely to experience positive psychological effects of having donated. ²⁰ A prospective, multi-institute investigation revealed that post-transplantation, 56% of 16 sibling donors aged 9–22 years stated they benefited from donation, with only 1 of 14 sibling donors expressing regret post-transplant. ²¹

Perceived Choice

Studies reveal that sibling donors may perceive they have no choice in becoming a donor. A qualitative study of 15 siblings at a single institution revealed that five siblings felt as though the doctors and family members limited their opportunity to say no, perceiving that they had no choice due to external influence. In this same study, nine siblings felt that saying “no” was not an option due to their own beliefs about life. ²⁰ In a three-time point survey of family members of a child scheduled to undergo hematopoietic cell transplantation (n=119 participants), 76% of interviewees perceived there was no choice in the decision to perform HLA typing of siblings, and 77% perceived no choice in whether they would donate to a sibling, ²¹ presumably because transplantation was a potentially life-saving intervention.

At-Risk Siblings

Biomedical markers objectively demonstrate that siblings weighing <20 kg are at higher risk of medical complications. ²² However, the risk to the psychologically vulnerable adolescent-age sibling is much harder to quantify, as the baseline psychosocial functioning of the family and the sibling “role” in the family certainly factor into resilience and outcome. ²³ As formation of social identity and decision-making maturity are salient aspects of adolescent development, the sibling donor's maturation must be considered as part of psychosocial donor assessment and care. Poor psychological functioning in donors appears to be related to age, with a noted risk of unresolved developmental crises during adolescence. ²⁴ A poor or burdened medical outcome for the patient, including graft-versus-host disease or death, has consistently proven to increase risk to the psychological health of sibling donors.^18,20 Modifiable factors documented as influential in sibling psychological outcome include: amount of preparation for transplant complications, duration of separation from sibling, level of involvement in donation decisions, and perception of choice versus perception of coercion. ²⁴

In the deepest shadow stands the nondonor sibling, already at risk by virtue of having a sibling with a chronic life-threatening illness^23,25 and perhaps at additional risk by not having the benefit of feeling a sense of purpose or contribution toward their sibling's wellness. In a study of 23 nondonor siblings aged 6–18 years for surviving pediatric bone marrow transplant recipients, nondonor siblings showed significantly more school problems than donor siblings, and one third of nondonor siblings reported a moderate level of post-traumatic stress reaction. ²⁴

Ethics

Although one could argue that all humans (including young children) exist within an interconnected social network where members owe at least some duty to protect and enhance the welfare of others, this notion of altruism should not supplant attentiveness toward the burden or risks to the sibling who is being asked to donate. Some apply a utilitarian analysis to these situations and argue that the proper course is that which results in the greatest net benefit, even if this imposes an asymmetry of risks/benefits upon certain family members. Others argue from a deontological perspective that sibling donation is ethically justified, and even required, as part of a larger familial duty. ²⁶ On the other hand, deontological ethical theories would also give priority to individual rights and argue that the welfare of the donor must be taken seriously, and that it would be wrong to use one person (such as the donor) solely as a means to optimizing the welfare of another (the recipient). These ethical considerations must be carefully weighed, and may be complicated by the unique features of transplantation. For example, while an anticipated benefit of transplantation for the recipient may be considered a compelling reason to justify hematopoietic cell donations from adolescent siblings, the final outcome is not always the one hoped for, and outcomes are not always successful. If the transplanted sibling dies, the adolescent sibling may also suffer the harm associated with feelings of guilt and failure.

Similarly, one argument supporting sibling donation is the principle of intimate attachment, in which life is diminished when a loved one suffers, and thus a sibling's best interests are honored by being allowed to serve as a donor for their sibling. ²⁷ The intimate relationship between family members creates special obligations to one another, and when combined with the greater likelihood of survival and decreased suffering of the sibling recipient, provides the general ethical justification for sibling stem cell donation, including those situations in which the donor is a minor ²⁸ Yet, duties within families must have limits, and while aspirations of future family intimacy should guardedly factor into present responsibility for one another's future welfare, the weight given to this factor depends somewhat on the existing bonds between the siblings being reasonably intimate and positive.^29–31 Attending to what is important in the various ethical theories requires attention to the welfare of both the donor and the recipient. At a minimum, an ethical duty exists to optimize the welfare of the donor by minimizing potential harms, eliciting and respecting the donor's feelings and opinions about donation, and honoring their ultimate choice.

Professional Statements

In 2010, the American Academy of Pediatrics provided a statement that minor hematopoietic progenitor cell donation from siblings is ethically permissible with the following met conditions: there is lack of medically equivalent adult relative; there exists a strong personal and positive relationship between donor and recipient (or such may be anticipated); the existence of some likelihood of anticipated benefit to the recipient; that the clinical, emotional, and psychosocial risks to the donor are minimized and reasonable in relations to the benefit expected to accrue to the donor and recipient; and that parental permission and donor assent be obtained. ³² In addition, this policy suggested that an independent donor advocate or similar mechanism for minor sibling hematopoietic donors, the established standard in solid organ transplant, be implemented in these cases. The AAP suggested that a donor advocate or similar mechanism should be involved at the onset, be independent of the team responsible for the direct care of the transplant recipient, bring expertise in pediatric development to facilitate donor education and inclusion, and possess the authority to postpone or prohibit donation if the donation is likely to have a serious and sustained long-term adverse impact on the donor, up until onset of recipient myeloablative conditioning. While the idea of requiring of a donor advocate was controversial in the pediatric oncology community, ³³ its intent was to assure that the welfare and rights of the donor not be overshadowed by concern for the recipient.

Opportunities for Clinical Teams

By understanding the unique developmental needs of adolescent sibling donors, care teams may better design implementation strategies that ensure a successful transition to adulthood regardless of sibling recipient outcome. The essential step in determining the best way to minimize harms specific to adolescent siblings of transplant recipients is to bring the siblings out of the shadow, primarily by giving voice to sibling experiences through investigation into sibling donor perspectives. Research has revealed that adolescent and young adult siblings of patients with cancer have a perceived decrease in the quality of relationships with parents and others when they have a higher level of unmet needs during their sibling's cancer diagnosis. ³⁴ A focus on adolescent sibling donor needs honors cancer patients, as cancer patients affirm that honoring their family members mutually honors their own care needs. ³⁵ Further research is needed to compare the needs of being an adolescent sibling donor versus a sibling nondonor so as to respond to the unique risks inherent in both roles while adapting to the uniqueness of each sibling within the family context. A prospective, multi-institutional investigation revealed that post-transplantation, 4 of 16 of sibling hematopoietic stem cell donors wished they had been given more information, ²¹ thus emphasizing the longitudinal opportunity to check in with siblings to determine whether the level of information being provided meets their current needs. In a qualitative study of bone marrow donor siblings, seven themes emerged: (1) include me in the definition of “family,” (2) be caring, (3) share information with me, (4) give me choices, (5) help me share my feelings, (6) provide opportunities for me to meet my peers, and (7) create a healthy hospital environment. ³⁶

Among the tangible day-to-day steps that the care team can perform to honor sibling donors is to be cognizant of language. For example, knowledge of sibling guilt in graft-versus-host disease makes it essential that comments about cells are depersonalized, so as not to suggest that “your sister's cells are attacking your body's cells.” A far better approach would be to suggest that “immune cells in the graft recognize host cells as foreign and are working hard to bring a strong defense” (or a similar depersonalized analogy). Recognizing the decisional conflict faced by parents and the common perception among donors that they lack any true choice should lead providers to use language that is more inclusive and inviting and less suggestive and potentially coercive. ³⁷

Many medical institutions now assign child life specialists to bone marrow transplant sibling donors for education, preparation, and support. Services for nontransplant siblings include normalizing activities and therapeutic interactions. A transplant center developed a program to assist sibling donors with psychological and emotional distress, including involving the sibling's participation in age-appropriate medical play and discussions of feelings and concerns. ³⁸ Whether through sibling support programs or educational materials, the health community has opportunity to define best practices for sibling donation as centers vary tremendously in approach.

Conclusion

The term “shadow” conceptualizes a shape cast on the surface by the interception of a body coming between light rays and an oblique body. A shadow remains a shadow only so long as there is a screen or block between the viewer and form. A national longitudinal commitment to study effective interventions further for improving the long-term medical and psychosocial impact of adolescent sibling hematopoietic transplant donation has important potential. Further investigation into best practice interventions has potential to shed light on the development of specific support for this generally overlooked but remarkably generous, brave, and invaluable population.