Ethical and Analytic Challenges With Genomic Sequencing of Relapsed Hematologic Malignancies Following Allogeneic Hematopoietic Stem-Cell Transplantation
2Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
3Division of Pediatric Cardiology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
4Genetics and Genome Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
5Stem Cells, Canadian Blood Services, Ottawa, Ontario, Canada
6Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
7Centre of Genomics and Policy, McGill University, Montreal, Quebec, Canada
8Childhood Cancer Canada, Toronto, Ontario, Canada
9The Department of Bioethics, Dalhousie University, Halifax, Nova Scotia, Canada
The implementation of precision medicine and next-generation sequencing technologies in the field of oncology is a novel approach being more widely studied and used in cases of high-risk primary and recurrent malignancies. Leukemias are the second most common cause of cancer-related mortality in children and the sixth most in adults. Relapsed leukemia represents a major component of the population that may benefit from genomic sequencing. However, ethical and analytic challenges arise when considering sequencing of biologic samples obtained from patients with relapsed leukemia following allogeneic hematopoietic stem-cell transplantation. Blood from the recipient after transplantation would include donor-derived cells and thus, genomic sequencing of recipient blood will interrogate the donor germline in addition to the somatic genetic profile of the leukemia cells and the recipient germline. This is a situation for which the donor will not have typically provided consent and may be particularly problematic if actionable secondary or incidental findings related to the donor are uncovered. We present the challenges raised in this scenario and provide strategies to mitigate this risk.
Despite major progress in treatment, leukemia contributes to 20% of cancer-associated mortality in children, second only to brain tumors, and contributes to approximately 3%-4% of cancer-associated mortality in adults. Allogeneic hematopoietic stem-cell transplantation (HSCT) is one therapeutic option for individuals with relapsed or refractory acute lymphoblastic leukemia (ALL) and high-risk or relapsed acute myeloblastic leukemia (AML).1-3 Molecular profiling in oncology is becoming more frequently used in the hope of identifying driver mutations that may predict response to molecularly targeted drugs. Examples of such targets include the presence of internal tandem duplication in the FMS-like tyrosine kinase 3 (FLT3) gene, which may predict response to treatment with sorafenib4 or BCR-ABL1 that predicts response to imatinib or other ABL1 tyrosine kinase inhibitors.5 Patients who had a myeloablative allogeneic HSCT with good donor engraftment typically maintain donor hematopoiesis even in the setting of relapse. Thus, performing genomic sequencing of relapsed leukemia samples from patients who are postallogeneic HSCT necessarily must consider that donor DNA will also be sequenced. This leads to a variety of ethical and analytic challenges, which are superimposed and further magnify the challenges inherent in interpreting and reporting results of high-throughput genomic testing.
Broad genomic sequencing is increasingly being incorporated into the care of oncology patients. Its complexity is amplified in patients with relapsed leukemia after allogeneic hematopoietic stem-cell transplantation, who often maintain donor hematopoiesis. We explored the ethical and analytic challenges raised in this scenario, which consider that donor DNA will also be sequenced.
We present a thorough discussion of ethical considerations, with specific focus on the potential for unanticipated discovery of actionable genomic findings in the hematopoietic stem-cell transplantation donor. We provide an assessment of analytic options to mitigate this risk and present a number of potential solutions that aim to assure the rights and interests of donors are protected, while maintaining the opportunity to provide novel treatment options for patients with relapsed leukemia.
These issues and recommendations affect a number of stakeholders, including bone marrow donor registries, transplanters, oncologists, geneticists, and centers for genomic sequencing.
A central component of precision oncology entails sequencing genetic material from cancer cells, commonly together with a patient's healthy (germline) tissues, and using the results to determine potentially effective treatment, as well as interrogating the biology of the tumors.6-9 Precision oncology approaches have been incorporated as a standard of care for management of many types of tumors such as melanoma and non–small-cell lung cancers10 and principally remain as research endeavors in other cancers including childhood cancer. Reports describe the presence of actionable somatic targets in 34%-50% of analyzed pediatric cancer cases and germline mutations associated with cancer predisposition in approximately 10%-15%.11,12 A review of genomic characteristics of relapsed pediatric B-cell ALL showed the presence of aberrations that may predict response to glucocorticoids (such as those in the glucocorticoid receptor gene NR3C1 and the CREBBP acetyltransferase gene) or response to thiopurine (NT5C2).13 In addition, aberrations in the Ras pathway, cell cycle regulatory pathways, and histone acetylation and other epigenetic pathways are recurrently observed and could be theoretically targeted by small molecule inhibitors.13,14 Therefore, relapsed leukemia appears to be a strong candidate for identifying druggable targets, supporting the rationale to sequence these malignancies.15
Several ethical, analytic, and interpretive challenges associated with genomic sequencing in research and in clinical practice have been explored and described in the literature.16-19 For example, the process of identifying and reporting secondary or incidental findings requires careful consideration of ethical concepts related to autonomy (including the right not to know and the right to an open future for children), beneficence, and respect to individuals.20-22 In the Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct to-Consumer Contexts report, the Presidential Commission for the Study of Bioethical Issues define incidental findings as results that arise that are outside the original purpose for which a diagnostic test or procedure was conducted, whereas a secondary finding is a finding that is actively sought by a practitioner that is not the primary target.23 In addition, there may be disagreement in the classification of the pathogenicity of a variant and in interpreting its clinical significance. The finding of variants of uncertain significance adds an interpretive challenge and complexity to the situation.24 Furthermore, in the context of genomic testing of hematologic malignancies, there may be difficulty in accurately identifying somatic changes in malignant cells versus germline changes.25
In the context of sequencing a patient's cancer that has relapsed following HSCT, there is a risk of detection of donor genetic material from blood or other tissues, including from the buccal tissue of the recipient.26 The implications of this have not been explored in the literature in the context of genomic sequencing and raise the spectre of identifying actionable genetic findings without prior informed consent of the donor. The American College of Medical Genetics and Genomics (ACMG) has published guidelines for detection and reporting of secondary findings that are genomic variations with clinical significance that have actionable implications.27 Although these guidelines are considered controversial by some, they speak to testing in a clinical context and currently include a list of 59 genes that is periodically updated. Assuming that bone marrow donors represent healthy individuals from the general population, the risk of discovering one of these actionable genes is estimated to be approximately 1% of cases.27
The discovery of potentially actionable findings is complicated further by these studies being conducted in a research context without the usual stringent quality control mechanisms required in clinical laboratories, although many laboratories today conduct testing in Clinical Laboratory Improvement Amendments (CLIA) or CLIA-equivalent–approved settings.20
There is currently no formal guidance about addressing incidental or secondary genomic findings attributable to the donor. The main alternatives to address this issue are all unsatisfactory: (1) to withhold genetic information from the donor that may be potentially relevant to them; (2) to disclose an increased risk of future genetically determined disease without prior explicit consent, or (3) to informatically filter out donor variants in advance of displaying sequencing data; this latter option requires genomic sequencing of donor material for which the donor had not consented and may place a moral burden on the informatics team, who may nonetheless be privy to the donor DNA sequencing results.28
In this commentary, we discuss the ethical and analytic challenges with molecular profiling through high-throughput DNA sequencing that may be encountered in patients who had received HSCT and provide recommendations to mitigate these challenges.
The following three case studies have been created to illustrate some of the technical and ethical challenges encountered in this setting.
A 29-year-old woman with a history of high-risk AML had a relapse a few months after receiving an allogeneic HSCT from a matched unrelated donor. She was enrolled in a molecular profiling research study that revealed the presence of FLT3-internal tandem duplication variant in the AML cells, which can be targeted by the drug sorafenib. In the process of this testing, a pathogenic variant in the mismatch repair gene MLH1 was found. Simultaneous sequencing of the patient's own pretransplant stored germline DNA sample showed the absence of the pathogenic MLH1 variant, which suggests the possibility of the presence of Lynch syndrome in the hematopoietic stem-cell donor (with cumulative cancer risks as high as 50% for component tumors).29 This case highlights the need for informing donors about the possibility for genomic sequencing of the recipient, which may detect actionable information about the donor's health, and the need to discuss the donors' preferences for return of incidental or secondary findings.
A 17-year-old man with history of high-risk ALL treated with cord blood stem-cell transplant 10 years ago is found to have a late bone marrow relapse. The patient participated in a molecular profiling study to determine whether he would be a candidate for a trial of a targeted therapeutic agent. Genomic testing of the leukemic relapse showed a pathogenic variant in the LDLR gene suggesting familial hypercholesterolemia. Testing of a skin biopsy from the patient showed the absence of the LDLR mutation, indicating possible origin of the LDLR gene variant from the cord blood donor. Informed permission for germline sequencing and return of incidental or secondary findings had not been obtained or discussed with the donor's parents. This case also raises the question of assent for receipt of genomic findings by the maturing donor (now 10 years of age).
A 7-year-old boy with a history of Shwachman-Diamond syndrome received an allogeneic HSCT at age three years from his older brother because of high-risk AML. A few months after HSCT, the recipient developed relapse of his AML that was refractory to subsequent chemotherapy. Molecular profiling showed the presence of a pathogenic variant in BRCA1 in the sequenced AML sample that was not present in the recipient's normal tissue (skin biopsy). Family history did not suggest a cancer predisposition syndrome. The BRCA1 variant was suspected to originate from the donor DNA based on an analysis of its high variant allele frequency and the relatively low percentage of blasts in the blood sample sequenced. This case highlights the challenge of identifying an actionable finding in a donor that may be associated with risk to the parent that was not clinically known.
Below, we present the ethical principles that may guide management of the dilemmas encountered in these scenarios. We will also review some of the regulatory guidelines related to return of incidental or secondary findings following genomic testing, as well as discuss the literature describing methods to preserve the rights of donors to privacy and autonomy. Although the examples presented are created scenarios, the ethical and analytic challenges associated with sequencing patients in the post-HSCT setting have been encountered by the authors in the context of the national precision oncology program in Canada (PRecision Oncology For Young peopLE, [PROFYLE])30 and the SickKids Cancer Sequencing program at The Hospital for Sick Children, Toronto.31 Through iterative discussions with experts in genomics, HSCT, and research ethics, we developed approaches to begin to address these challenges locally. The following commentary and recommendations reflect the subsequent review and endorsement of the PROFYLE consortium, representing a national extensive array of adult and pediatric oncology, transplant, genomics, ethics, and patient advocate expertise. These recommendations are also supported by Canadian Blood Services, the national authority for the provision and coordination of blood products as well as organs and tissues across all Canadian Provinces, with the exception of Quebec.32
One of the cornerstone ethical aspects of the bone marrow donation process is the preservation of the rights and safety of donors. Although altruism is likely the principle motivation of most stem-cell donors, it is possible, and perhaps even probable, that the potential of future sequencing would not affect the decision making of the donor.33 Indeed, such a discussion could potentially enrich the decision-making process. Although studies on patients with cancer, their parents, and on the general population have shown that most are enthusiastic to receive information about their genome and possible implications on their health,34-36 the acceptance of future sequencing with its impact on the donor should not be assumed and thus should be included in the consent discussion. The World Marrow Donor Association (WMDA) has published several statements describing standards that aim to ensure donors are protected.37 The standards include the requirement that sufficient information is provided to the donor to ensure consent is fully informed, and this includes information about potential risks of donation. Statements by the WMDA37-39 do not explicitly contemplate the complexity of future sequencing of the recipient at relapse and the consequent risk of identifying incidental or secondary genomic findings originating from the donor. When discussing donor rights, WMDA acknowledges that reporting of information back to the donor about uncovered findings relevant to donor's health is an unresolved issue.37 Genetic counseling for recipients is suggested along the course of HSCT40 but we did not identify literature describing its utility for counseling donors before transplant. Other guidelines that address donor-related information (including donor-related malignancy or donor genetic illness such as Gaucher disease) recommend notifying the blood banks or registries to prevent potential harm by giving the same donation material to another recipient; these do not address the ethical question of returning actionable information to donors.41,42
The ACMG guidelines recommend that a discussion about the possibility of medically actionable incidental or secondary findings is routinely performed before any extensive genomic testing and that the patient's preferences for disclosure of such findings needs to be obtained before testing.27 By contrast, this discussion is not routinely made before the process of bone marrow donation. Given the barriers to communication in the immediate post-transplant period between the recipient's medical team and the donor (in cases of unrelated donors), it may be challenging to obtain post-HSCT consent for receipt of the results of genomic testing. Thus, anticipation of the possibility, and appropriate documentation of preferences for return of actionable genomic results by the donor, is much more preferable to be situated in the pretransplant consent process. It is recognized that once the stems cells are infused into the recipient, they no longer are under the control of the donor. However, this would not minimize the potential moral distress experienced by the treatment team in not offering profiling results that have potentially significant health implications to the donor.
In sequencing genetic material after cord blood HSCT and in some cases of related HSCT donation, the minor age of the donor deserves further consideration. First, it is important in those cases to differentiate findings that confer adult-onset disease risk (such as familial breast-ovarian cancer) or child-onset disease risk (such as Li-Fraumeni syndrome). Another consideration is that minor donors are confined by the informed permission provided by their parents or guardians. They typically do not have the capacity to consent to choose whether they would like to be informed of the results of genetic sequencing.43 Parents or guardians are generally considered to be the most appropriate advocates for the child's best interest. The literature about whether a child should receive results of genomic testing often hinges on the concept of an open future, where a choice to receive results or not is preserved. There is an argument that parents or guardians must be given and have an obligation to accept actionable genomic results that are directly relevant and actionable in childhood, as their first obligation is the best interest of the child.20 This argument has been expanded to consider the return of actionable adult-onset conditions where the life of a parent could be saved, as that also provides direct benefit to the child.20,43 Although controversy still exists in the literature regarding return of results of adult-onset conditions to children,44 it has been well established that clear guidance as to what may be returned should be part of the informed permission discussion.45,46
In cases of related donors, family members should also consider the benefit or risk to the family when addressing the question of whether to have genetic information disclosed. When the donor and the recipient are siblings, it is simpler to have the discussion before the sequencing process where the possibility of finding donor genetic material is addressed and the family's preferences could be discussed.43
With the increased availability and clinical utility of genome sequencing in medicine, we can predict with reasonable confidence that clinical genomic sequencing is going to become more commonly used as part of routine care, as it already has for some adult cancers. Therefore, it is reasonable to recommend a change in the predonation process by adding a discussion with potential HSCT donors about the possibility of having their genetic material sequenced, if the recipient subsequently undergoes genomic testing. In stating this, we do not imply that the donor can prevent molecular testing of this nature in the recipient, given the transfer of control via the transplant. However, we do advocate that this possibility be included in the discussion of the risks and benefits of donation and that there be documentation of the donor's choice to receive or not receive actionable genomic results relevant to their health. This same process should be implemented with parental donors of umbilical cord blood stem cells or those unable to consent for themselves, such as younger children, where informed permission had been provided by parents or a guardian.
Another important approach to consider is the incorporation of analytic and informatic processes, which may circumvent sequencing donor DNA or detecting donor variants. To eliminate donor genome sequencing while still obtaining the clinically relevant information about the recipient's cancer genome, a presequencing cell sorting technique, such as flow cytometry, may be used. Flow cytometry uses cell surface markers to separate mixed populations into its components, for example, leukemia cells and donor cells. It must also be considered that this capability may not be readily available at some cancer centers; furthermore, complete separation of the malignant and donor cells may not be absolute. Another approach to minimize detection of donor germline findings while sequencing a mixed (leukemia and donor cell) bone marrow sample is to limit bioinformatic analysis to subsets of genes that are known targets for therapeutic agents predicted to have antitumor effects. The difficulty in this approach is that certain targetable mutations can also be related to germline cancer predisposition syndromes, for example BRCA1 (targetable by poly [ADP–ribose] polymerase inhibitors); therefore, omitting such genes may lead to potentially targetable findings being overlooked.47 One may also attempt to bioinformatically filter all variants that are likely to be donor source based on their frequency in the sample (relative to the known percentage of leukemia blasts) and based on known population variants. This may be difficult to achieve with certain proportions of donor normal and blast combinations. This approach also carries the risk of inadvertently masking subclonal or minor clonal variants that are in fact related to the leukemia itself. In addition, if there is incomplete filtering, there is a risk of overestimating the mutational burden in the leukemia because of detection of variants arising from donor genome that are attributed to leukemia cells. Furthermore, even if donor-related variants could be filtered bioinformatically, we note that this leaves the informatics team with the moral burden of knowing these actionable findings are present but then ignored.
The most robust analytic strategy, which would clearly identify molecular changes that are leukemia-, recipient germline–, and donor germline–derived, is to directly sequence a source of donor DNA and recipient DNA, and to perform a subtractive analysis to isolate the variants that are unique to the malignant leukemia cells. The most acceptable source of donor DNA is a sample of the recipient's blood, taken after HSCT but before relapse if the patient engrafted with 100% donor-derived nucleated blood cells. This is legally permissible as the blood is now under the control of the recipient. This solves the challenge of sorting what is donor-derived and what is recipient-derived, but does not solve the moral dilemma of what to do with incidental actionable findings detected from the donor DNA. It should also be considered, in this circumstance, that the privacy of the donor should be respected and only actionable findings relevant to the recipient should be shared with the recipient.
Table 1 outlines some additional technical considerations, relevant to the sequencing of leukemia samples obtained from patients who are postallogeneic HSCT, including challenges encountered by using various sources for the normal (nontumor) genome (required for subtractive analysis). The major consideration differentiating recommended strategies versus those that are not is based on a primary goal of producing the most robust somatic (leukemia) analysis. A number of strategies were considered to be acceptable analytically, and the choice between these will depend on local resources and expertise. Some of these still have relevant shortcomings that must be considered.
We advocate for the prospective inclusion in the consent process that sequencing of donor-derived cells is possible in the context of preparing for or responding to a recipient relapse. While in many cases the consent to recontact donors is already part of the predonation process, a separate discussion about receiving more information relevant to their health through genomic testing is important to all donors. This would include discussion of potential risks and benefits of receiving such results, as well as documentation of preferences of the donor. An opt-out strategy for disclosure of incidental or secondary findings is suggested, as a number of studies have shown that most individuals—be they parents, patients, or the general public—wish to receive information about their genetics.34-36 It would also be necessary to establish a mechanism to support the sharing of this information. Reaffirmation of the wish to receive results should be sought at the time of disclosure. Although a clinician with an established rapport with the donor is encouraged to be part of the conversation, it is acknowledged that clinician confidence in genomics may be limited48; thus, the discussion should at a minimum include someone with expertise in genetic counseling and the disease predisposition gene being disclosed.45
For donor-recipient situations where consent for donor germline testing has not been previously considered and/or documented, we suggest the following:
(A) In cases of unrelated donor transplantation: If an actionable finding attributed to the donor's genome (as defined by the most current ACMG recommendations) is detected, reasonable effort will be made to convey the results through the donor registry to the primary physician of the donor to offer the information about the actionable findings. Donors may choose to decline the discussion and the disclosure of those findings. Any discussion of the actionable findings, if desired, should occur with the support of a genetic counselor or appropriate expert in the disease.
(B) In cases of related donor transplantation: Reasonable effort will be made to reach the donor or their guardian to offer the information about the actionable findings, which may be most practically achieved by the transplant team. This discussion should occur with the support of a genetic counselor or appropriate expert in the disease. The primary care physician should also be engaged. Donors may choose to decline the discussion and the disclosure of incidental or secondary findings, unless the disclosure is determined to meet the best interests of the child threshold.
The following recommendations and principles should also be considered:
Donor DNA should not be actively analyzed as a goal in and of itself; it may only be used to filter out sequencing variants that are not the acquired variants of the tumor.
If medically actionable genetic variants are incidentally discovered, efforts will be made to deliver this information back to the donor as noted above unless explicitly declined in the consent process.
Efforts should be made to minimize the risk of detection of donor-specific genetic markers by separating tumor cells or by using bioinformatic filtering strategies, where possible.
Donor-derived genetic information from a recipient's sample should not be disclosed to the recipient unless the finding is actionable in the recipient, as determined by clinicians with disease-specific expertise. Every effort should be made to obtain prior consent for such disclosure from the donor.
When the sequencing of the relapsed specimen is undertaken in a research setting, validation of the sequencing findings in a clinical laboratory (if available and approved in the donor's jurisdiction) must be undertaken. If feasible, confirmation of the findings in a clinical laboratory should be done before conveying the result to the donor. In addition, we suggest directly testing a sample from the donor to confirm the findings.
Material and/or raw data from post-transplant patients and sequencing data relevant to the donor should not be shared with anyone outside molecular profiling efforts, whether clinical- or research-based (ie, for other research, or deposited in scientific databases) because of the risk of donor identification without informed consent or informed parental or guardian permission.
In conclusion, as genomic sequencing becomes a more standard component of clinical oncology care, thoughtful consideration of ethical principles and analytic approaches are required to assure the rights and interests of donors are protected, while maintaining the potential promising benefit of novel approaches to treat patients with relapsed leukemia. Further research to explore the perspectives of donors and of other stakeholders on the recommendations herein as well as prospective studies describing the impact of their implementation would be valuable.
Supported by the Terry Fox Precision Oncology for Young People (PROFYLE) program and through funds from The Terry Fox Research Institute, Air Canada Foundation, Alberta Cancer Foundation, BC Children's Hospital Foundation, BC Cancer Foundation, CancerCare Manitoba Foundation, Charles-Bruneau Foundation, ChildCan, CHEO Foundation, CHU Sainte-Justine Foundation, Coast to Coast Against Cancer Foundation, Dalhousie Medical Research Foundation, Fight Like Mason Foundation, Garron Family Cancer Centre, IWK Foundation, Janeway Children's Hospital Foundation, Kids Cancer Care Foundation, London Health Sciences Centre, McMaster Children's Hospital, The Montreal Children's Hospital Foundation, Phoebe Rose Rocks Foundation, Sarah's Fund for Cedars, SickKids Foundation, SickKids Research Institute, and Team Finn Foundation.
Conception and design: Bilal Marwa, Joerg Krueger, Elizabeth A. Stephenson, David Allan, Adam Shlien, David Malkin, Conrad V. Fernandez, Anita Villani
Collection and assembly of data: Bilal Marwa, Joerg Krueger, Elizabeth A. Stephenson, Scott Davidson, David Allan, Adam Shlien, David Malkin, Conrad V. Fernandez, Anita Villani
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Consulting or Advisory Role: Novartis, Kite/Gilead, SOBI
Speakers' Bureau: Novartis
Travel, Accommodations, Expenses: Novartis
Elizabeth A. Stephenson
Consulting or Advisory Role: Medtronic, Abbott Diabetes, Insulet Corporation
Research Funding: Bank of Montreal
Other Relationship: Canadian Blood Services
Consulting or Advisory Role: Bayer
Consulting or Advisory Role: Bayer
No other potential conflicts of interest were reported.
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