Who owns that blood? Recontacting donors with results from genetic testing after allogeneic hematopoietic cell transplantation

Abstract

Chris Dobson, a 17-year-old male, was transplanted for acute lymphoid leukemia (ALL) from a female matched unrelated donor. Eight years post-transplant, Chris presents with progressive pallor and fatigue and is diagnosed with acute myeloid leukemia. Clinical genomic testing reveals 100% donor chimerism and a likely pathogenic BRCA1 mutation, presumably donor-derived. This finding is significant for his female donor, as BRCA1 mutations increase breast and ovarian cancer risk, warranting early screening and preventive options. However, her preference for receiving such information is unknown.

Alba Beyaz, a 23-year-old female, joins a cancer survivor genomics study. Ten years ago, she received hematopoietic cell transplantation (HCT) from her younger sister, who is now 18. Alba, currently healthy, donates a blood sample for whole exome sequencing of clonal hematopoieis (CH). Results reveal a likely pathogenic DNMT3a mutation in 30% of reads. While having this mutation does not change Alba's current health, CH is linked to several long-term health risks in the general population. While Alba opted to receive her results, the preference of her sister, the HCT donor, is unclear.

Recent advances in next-generation sequencing and bioinformatics have significantly expanded our understanding of normal and malignant hematopoiesis. Within the context of clinical allogenic hematopoietic cell transplantation (allo-HCT), genetic tests provide a sensitive means to monitor post-transplant donor chimerism and minimal residual disease and analyze the mutational drivers of relapse or donor-derived malignancy after transplantation. Some of these tests, such as sequencing-based evaluation of HCT donor chimerism, are already standard clinical practice in many centers, with others rapidly approaching clinical application. Additionally, advances in (single-cell) genomic technologies are increasingly being used in scientific research aimed at dissecting the mechanisms of post-transplant hematopoieis.^{1, 2}

While holding significant clinical and scientific potential, genomic tests can yield both expected and unexpected results beyond the target information. Following HCT, genetic testing may uncover genetic information of donor origin, including germline and somatic mutations. While the majority of genetic aberrations are non-functional, some may contribute to an increased risk of disease. Depending on the specific aberration, whether it is germline or somatic, and whether it occurred before or after HCT, its identification may be relevant for the HCT recipient, the donor, or both. For example, germline variants associated with hematologic malignancies (e.g., ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, and UBA1) are relevant for both parties. In contrast, germline variants associated with non-hematologic cancers, such as BRCA1, primarily impact the HCT donor. Finally, somatic clonal mutations in leukemia-associated driver genes (CH) are common after HCT, and their clinical relevance remains a topic of the ongoing investigation.^{3, 4}

The fictitious cases presented earlier highlight some of the dilemmas associated with genetic testing after HCT, particularly concerning ownership, informed consent, and donor recontact. Addressing these dilemmas requires a well-considered approach. However, specific guidance on donor information and recontact is currently limited and existing practices vary, representing a critical unmet need.^{5, 6}

Ethical dilemmas related to genetic testing have been widely acknowledged.^7-9 General principles for the responsible communication of results can be derived from international legislation and guidelines outside the transplant setting. However, a 2015 systematic review demonstrates that clear legislation on recontacting in clinical genetics is lacking.⁸ Additionally, an international analysis of rules governing the return of genomic results in research identified a variable landscape of laws and regulations, often inconsistent and sometimes contradictory.¹⁰ Moreover, existing guidelines are not sufficiently specified for HCT, where part of the analyzed material can be donor-derived. To begin addressing this gap, the World Marrow Donor Organization recently published recommendations on recontacting unrelated adult HCT donors on post-transplant genetic findings of potential donor origin.⁵ This landmark document addresses regulatory fragmentation across countries and provides general guidance for transplant registries. However, it does not address the unique ethical and clinical complexities of related donors or those who were minor at donation, including cord blood donors.

In the context of allo-HCT, a wide spectrum of genomic tests is used for both clinical and research applications. These include sequencing-based HLA typing, assessment of donor chimerism, monitoring for relapsed leukemia, and characterization of second malignancies. Beyond clinical use, genetic tests hold tremendous potential for scientific research aimed at understanding and improving allo-HCT outcomes.^1-4 Bulk and single-cell DNA sequencing offer unparalleled resolution to dissect genetic heterogeneity within the initial and relapsed cell populations, identifying potentially treatment-resistant subclones. Single-cell DNA sequencing has also been used to identify HCT-associated genotoxic exposures.² Additionally, single-cell RNA sequencing and its integration with other “omics” approaches provide a comprehensive view of the cellular and molecular processes that drive successful hematopoietic regeneration and post-HCT relapse.^{11, 12}

Addressing the ethical issues of recontacting HCT donors requires a clear definition of its scope. First, “recontacting” must be distinguished from “follow-up.” Recontacting refers to reaching out to individuals who are no longer in an active healthcare relationship but whose clinical and genetic data remain accessible.⁹ In contrast, follow-up is part of routine clinical care, including medical interventions and information provided to patients. Distinguishing between these two is particularly complex in the HCT setting, as HCT donors are not traditional patients and don't have a personal healthcare need. Additionally, routine clinical care and follow-up of HCT donors vary widely.⁹ Here, we define recontacting as re-establishing contact with HCT donors regarding new health-related information. Second, it is important to distinguish between genetic results obtained in research and care, which are traditionally governed by separate laws and guidelines. However, advances in personalized medicine have increasingly blurred this distinction.¹³ In this article, we aim to provide an integrated ethical framework for recontacting HCT donors, applicable in both clinics and research.

To summarize available guidance on recontacting individuals about genomic test results, we built on the systematic review performed in 2015.⁸ In addition, we incorporated four key international guidance documents published since: (1) the Global Alliance for Genomics and Health (GA4GH) Policy on Clinically Actionable Genomic Research Results¹⁴; (2) the GA4GH Consent Policy¹⁵; (3) the World Medical Association's Declaration of Taipei on Ethical Considerations Regarding Health Databases and Biobanks¹⁶; (4) the European Society of Human Genetics (ESHG) recommendations on recontacting patients in clinical genetics services⁹; as well as a donor disclosure framework⁶ and a decision-support tool¹⁷ for responsible recontacting in personalized oncology. Based on these documents, we identified core consensus principles relevant to recontacting HCT donors and identified existing controversies and gaps.

While general guidance documents show substantial overlap, the lack of harmonized international recommendations remains evident (Table 1). For instance, while GAGH and ESHG guidelines focus on actionable results,^{9, 14} the framework also recommends raising awareness of findings with unknown significance.⁶ Another unresolved issue is interpreting donor preferences for those who were minor at the time of donation, including umbilical cord blood donors. Furthermore, although some guidelines address the professional relationship between HCT donors and the genetic result holders, they do not always clarify recontact responsibilities. These gaps, along with the general ethical principles discussed earlier, inform our discussion and recommendations for comprehensive guidance.

Since the completion of the Human Genome Project in 2001, our understanding of the genetic determinants of health and disease continues to expand. This progress raises new challenges for responsibly sharing such information with HCT donors, especially in vulnerable situations involving minors and related donors in close contact with recipients.

As a general guiding principle, recontacting HCT donors should occur only when results are meaningful to their health or that of their relatives. While some argue that all results should be disclosed based on donor autonomy, this must be balanced against the duty to prevent harm and ensure proportionality. It is important to note that expanding the scope of recontact (e.g., by including significant findings of uncertain actionability) may introduce additional ethical dilemmas. For example, if Alba's sibling HCT donor was still a minor when the genetic finding is discovered, should only Alba be informed? Would it be realistic to inform Alba, but not her sister? And if not, what should prevail: honoring Alba's preference to receive the genetic information, or her sister's right to choose her preference when she reaches adulthood?

Determining which results warrant recontact is complex, as clinical significance is partly subjective and evolves with advancing scientific insights. For instance, in Chris's case, the findings are clinically actionable for the adult unrelated HCT donor, justifying recontact. In contrast, Alba's case is less clear, as the information might be relevant but not necessarily actionable. Defining clinical significance is essential, and collaboration between donor registries, clinicians, researchers and patients will be needed to establish these criteria.

One key gap involves recontacting adult donors (related and unrelated) when findings are clinically significant and actionable, but no preference for recontact has been recorded. In these cases, we recommend proceeding with recontact. Improved informed consent procedures at the time of donation can help reduce cases of unknown donor preference. A challenge arises when a related donor explicitly declines to receive findings, while the recipient and healthcare provider are informed. This creates a dilemma if the finding is clinically meaningful (important an actionable). We propose that in these situations, although challenging, the donor's right not to know should prevail. Ultimately, the responsibility to respect the rights of all parties involved is shared between the patient and the physician.

Another gap relates to minor donors. Recontacting these individuals for highly significant, actionable results is advised. However, when donor materials are anonymized (as is standard for cord blood donors), recontact is highly complicated or even impossible. For minors who donated for a relative (as in Alba's case), feasibility is rarely an issue, preferences often align, and clinically actionable results should be communicated. However, if the donor reaches adulthood before results emerge, their preference becomes relevant. Current guidelines offer little practical guidance on this. Re-assessing consent for all donors at adulthood seems disproportionate, as this will only prove relevant to a minority. A well-balanced individualized approach, involving doctors, geneticists, and potentially ethicists, will remain key to optimize care for both recipient and donor.

In conclusion, genomic testing presents unprecedented opportunities to improve our understanding of HCT and improve clinical outcomes. However, such tests are not without risks. Establishing clear policies for recontact ensures ethical integrity, protects donor rights, health, and well-being, and maintains public trust in HCT donation. These principles are essential for responsibly harnessing the evolving potential of genomic testing in the HCT context.

Conceptualization: Mirjam E. Belderbos, Marc Bierings, and Ghislaine J. W. M. van Thiel. Investigation of the literature and summary of findings: Mirjam E. Belderbos, Noa van Bergeijk, and Ghislaine J. W. M. van Thiel. Synthesis of evidence: all authors. Writing, review, and editing: Mirjam E. Belderbos, Marc Bierings, and Ghislaine J. W. M. van Thiel. All authors read and approved the final version of the manuscript.

The authors declare no conflict of interest.

M. E. B. receives funding from the European Research Council (project number 101114895), the Landsteiner Foundation for Blood Research (project 2305F), and KiKA (project number 418).