Ethical considerations in pediatric BMT donors and recipients.

Just over 25 years ago, an 8-year-old girl with acute myelogenous leukemia (AML) who coincidentally had sickle cell disease (SCD) underwent a successful matched sibling donor bone marrow transplant (BMT) for her leukemia from her otherwise healthy brother who had sickle cell trait. This was the first time that BMT had been shown to “reverse” SCD even though SCD was not the indication for BMT [1Johnson F.L. Look A.T. Gockerman J. et al.Bone marrow transplantation in a patient with sickle-cell anemia.N Engl J Med. 1984; 311: 780-782Crossref PubMed Scopus (224) Google Scholar]. A few years later, Lucarelli et al. [2Lucarelli G. Galimberti M. Polchi P. et al.Bone marrow transplantation in patients with thalassemia.N Engl J Med. 1990; 322: 417-421Crossref PubMed Scopus (539) Google Scholar] published results of BMT in children with β-thalassemia major, demonstrating 87% thalassemia-free survival in patients with Class 1 thalassemia. A subsequent national trial of BMT for SCD using matched sibling donors initiated in 1991 showed promising results with 55 of 59 recipients surviving, 50 of them free of SCD [3Walters M.C. Patience M. Leisenring W. et al.Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia.Biol Blood Marrow Transplant. 2001; 7: 665-673Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar]. Despite these promising outcomes, to date, only a few hundred children have undergone BMT for SCD despite the fact that there may potentially be thousands of eligible children with severe SCD and available allogeneic donors. There are many factors that contribute to this significant disparity between numbers of transplants and eligible patients. Although children with SCD demonstrate a variable phenotype with only 7% to 20% having the severe phenotype, the progressive organ damage that occurs in many patients contributes to a poor quality of life, rapid decline in survival during early adulthood, and a significant risk for premature mortality. Thalassemia major, on the other hand, has a much less variable clinical course, with most patients requiring regular blood transfusions starting in late infancy or early childhood. Allogeneic BMT from either a matched sibling or unrelated donor has become the “standard of care” for β-thalassemia major. This is also true of other inherited diseases of the lymphohematopoietic system such as Wiskott-Aldrich syndrome where early BMT soon after diagnosis is now recommended when a well-matched allogeneic donor is available. Yet, among patients with SCD who end up on chronic transufusion therapy because of severe SCD-related morbidity, many who have matched sibling donors do not undergo BMT. Whereas unrelated donor BMT has been carried out for thalassemia and WAS since the 1990s, it has been considered experimental for children with SCD and is only recently being investigated in a clinical trial setting. It is worth exploring why the application of this “curative” therapeutic approach to SCD is different than in thalassemia and perhaps considering a paradigm shift. Based on the experience with children with inherited primary immune deficiency diseases who have now been followed for almost 4 decades after BMT, there is no reason to believe that patients with SCD who undergo BMT will not derive a long-lasting benefit. Mounting evidence points to resolution of SCD-related symptomatology and stabilization or improvement of organ function after successful BMT for SCD. Long-term complications such as sterility and a slightly increased risk of cancer aside, BMT survivors should be “cured” of their underlying hemoglobinopathy. The medical literature is rife with articles that talk of cure of thalassemia by BMT, yet this term is infrequently used for SCD and BMT. Most contemporary informational and educational brochures on SCD rarely mention BMT as a therapeutic option. A recent publication from the Centers for Disease Control and Prevention states “Symptomatic treatments exist, but there is no cure for SCD.” The parents alert brochure for those whose children have screened positive for SCD from the Texas Department of State Health Services states that “there is no cure for SCD but with penicillin and good care, most serious infections and almost all the deaths in young children can be prevented.” The guidelines for the management of SCD complications for healthcare providers from the SCD Care Consortium (supported by the Texas DOH), however, states: “Successful allogeneic hematopoietic stem cell transplantation provides a hematologic cure for SCD.” The FAQ section on the Website of the SCD Association of America, Inc. (a leading community SCD organization) makes no mention of BMT, and categorically states that there is no universal cure for SCD, but that research in gene therapy, the ultimate universal cure, is underway. This dichotomy between the information provided to healthcare teams on the one hand and to the patients, parents, and the lay public on the other lends credence to the perception that medical paternalism has long been practiced in the management of this disease. Surveys of adults with SCD and of parents of children with SCD have shown that there is no agreement between the recommendations of healthcare providers and the risks that patients and parents are willing to accept to obtain a “cure” for their disease. In view of the substantial patient interest in curative therapy, the authors recommended that education about and consultation for BMT in patients with SCD be encouraged [4Kodish E. Lantos J. Stocking C. et al.Bone marrow transplantation for sickle cell disease—a study of parents’ decisions.N Engl J Med. 1991; 325: 1349-1353Crossref PubMed Scopus (110) Google Scholar, 5Besien K.V. Koshy M. Anderson-Shaw L. et al.Allogeneic stem cell transplantation for sickle cell disease. A study of patients’ decisions.Bone Marrow Transplant. 2001; 28: 545-549Crossref PubMed Scopus (62) Google Scholar]. During the conduct of the national matched sibling donor trial for SCD, Walters et al. [6Walters M.C. Patience M. Leisenring W. et al.Barriers to bone marrow transplantation for sickle cell anemia.Biol Blood Marrow Transplant. 1996; 2: 100-104PubMed Google Scholar] looked into the barriers to BMT. Although the lack of an HLA-identical sib donor was the major barrier, physician refusal was more frequently encountered than parent refusal. The increasing availability of well-matched unrelated donors should alleviate the most significant barrier to BMT for eligible patients with severe SCD. With the ever increasing exposure to media and wide availability of access to the Internet, more and more patients and families are empowering themselves with scientific information in order to reject medical paternalism. Patient and parent education and empowerment and an honest discussion of risks, BMT outcome uncertainties and benefits of BMT should be fostered. A report by Smith et al. [7Smith L.A. Oyeku S.O. Homer C. et al.Sickle cell disease: a question of equity and quality.Pediatrics. 2006; 117: 1763-1770Crossref PubMed Scopus (105) Google Scholar] details the important gaps that exist in the equity of funds (both federal and private sector) allocated to research and in the implementation of advances in clinical care for sickle cell disease compared to cystic fibrosis. Although mortality in children with SCD has significantly decreased over the past 4 decades, the widespread adoption of best clinical practices and quality improvement efforts have lagged behind. This is especially true for adults with SCD for whom removing barriers of access to health insurance and implementation of quality comprehensive care can improve quality of life and survival. In order that parents of children with SCD are made aware of not only the uncertain prognosis for their child but all potential therapeutic options at the time of diagnosis, it is important to include accurate information detailing the role of BMT, its indications and potential toxicities, in parent brochures and education. This is an important consideration in the paradigm shift. As physicians, our Hippocratic oath tells us: Primum non nocere, or first, do no harm. Does this only mean not considering a therapeutic option that may be potentially fatal? Are we perhaps not doing harm by not offering a potentially curative therapy and subjecting the patient to a lifetime of morbidity, decreasing neurocognitive function, poor quality of life and the prospect of premature lethality? The ethical challenges of offering a potentially curative therapeutic option with a small but finite risk of treatment-related mortality in a disease where the patient and family are not faced with the prospect of mortality in the short term (unlike refractory leukemias or severe aplastic anemia) are clearly difficult and fraught with controversy. Both the patient and family and the healthcare team have to be willing to accept this mortality risk in exchange for potential cure. This ethical dilemma is explored in more detail below. SCD and thalassemia are 2 nonlethal conditions in which a bone marrow transplantation cures the disease. The 2 offer interesting contrasts that shed light on the ethical paradigms that govern the use of BMT for nonlethal conditions. Both β-thalassemia major and SCD can be reliably diagnosed. The clinical course in SCD, however, can vary widely. Some children have virtually no sequelae or complications from their disease. Others are debilitated by strokes, acute chest syndrome, or recurrent vaso-occlusive crises. Life expectancy is lower in β-thalassemia than in SCD disease and is more heavily dependent upon the availability of hypertransfusion and chelation. The severity of the disease and the lack of variation in clinical course make the decision to transplant children with thalassemia less controversial, particularly if they have a sibling who is an excellent match. By contrast, the variable course in SCD makes it crucial to rely upon prognostic factors other than the diagnosis itself. Children with SCD do not become eligible for BMT unless they have other morbidity. Even then, the decision is complicated. To offer BMT for SCD, doctors must understand that they are offering a treatment that has a chance of significantly shortening the patient’s life. The ethical challenges of evaluating such a proposed therapy are daunting. SCD is a chronic disease that is usually not immediately life threatening. Today, in the United States, most patients with SCD survive well into adulthood. Some, however, have significant morbidity from their disease. The most worrisome morbidities are from either strokes or from recurrent vaso-occlusive pain crises. Strokes can leave people seriously debilitated. Pain crisis sometimes require dozens of hospitalization each year with frequent use of high doses of narcotic analgesics. How does one balance the risks and burdens of the disease against the risks of treatment? Who should do the balancing? One of the interesting features of transplant decisions for patients with SCD is that patients seem willing to take more risk for a chance to cure their disease than doctors or institutional review boards (IRBs) are willing to allow them to take. Kodish et al. [8Kodish E. Lantos J. Siegler M. et al.Bone marrow transplantation in sickle cell disease: the trade-off between early mortality and quality of life.Clin Res. 1990; 38: 694-700PubMed Google Scholar] studied parents who had children with sickle cell disease, using standard reference gamble techniques. These techniques present parents with a gradually increasing level of risk, both for mortality from a transplant and morbidity from graft-versus-host disease (GVHD). A third of parents were willing to accept a 15% short-term mortality risk for a chance at cure. Thirteen percent would accept that plus a 15% risk of GVHD. Many IRBs consider any risk of death above 5% unacceptable. There are no studies of children’s own views, but 15% of adults with SCD are willing to accept a mortality risk of 35% for a chance at cure. Actual outcomes, for carefully selected patients, are an overall mortality rate of about 7% with event-free survival rates of 85%. These numbers suggest that we either underestimate the burden of SCD or have standards of acceptable risk for patients that are much more cautious than the standards that they would make for themselves. These studies raise questions about patient autonomy, about professional integrity, about the possibility of truly informed consent, and about the proper locus of responsibility for decisions such as this one. Three factors shape any decision to offer BMT for a nonlethal condition. First, how bad is the health-related quality of life for the people with the disease? Second, are there any prognostic factors that allow more accurate predictions of the clinical course for individual patients—that is, if we knew which patients with SCD were most likely to have debilitating strokes or vaso-occlusive crises, we could selectively transplant them rather than others. Finally, we must consider the likelihood of success or failure of the transplant and do so in light of the quality of the match that is available. These factors then lead to a 2-stage decision process. First, doctors must decide if they are willing to even offer a transplant. There may be situations in which parents or patients want a transplant but in which doctors feel it is too risky. We know from studies of practice variation between centers that different groups of transplanters have different thresholds of risk and benefit. If doctors are willing to offer a transplant, then parents and patients must participate in a rigorous process of informed consent. This is, after all, a more elective treatment than some. Meticulous attention to patient understanding is crucial. It may take time, but, given the nature of the disease and the treatment, there is time. The informed consent process needs to deal with some issues that go beyond merely the statistics on prognosis with and without transplant, mortality risks, or the risks (and nature of) GVHD. One of the issues concerns timing of the transplant. Generally, outcomes are better when transplants are done earlier in life. Generally, prognostic accuracy is worse early in life. A program of early transplantation will result in the transplantation of some children who may not have needed it, but will likely lead to better outcomes overall for the population of transplanted children. A related issue concerns preservation of fertility. Generally, transplantation leads to infertility. For BMT recipients who have gone through puberty, fertility can be preserved by harvesting sperm or ova for later use in an in vitro fertilization setting. Transplantation prior to puberty does not allow this option. This, too, must be factored into the decision, along with other variables that favor either early or late transplantation. In this transplantation situation, as in others, the donor faces a set of challenges that may be underestimated or ignored by the transplant team. Donation is not without risk, even though the risk is relatively low. More importantly, donors have well-described psychologic problems. They may feel used, neglected, or, if the transplant fails, guilt-ridden. A recent survey of HCT centers in the United States revealed that transplantation physicians were involved or potentially involved in overlapping care of the hematopoietic cell transplant (HCT) donor and the recipient in >70% of centers with similar practices for both adult or pediatric donors and recipients [9O’Donnell P.V. Pedersen T.L. 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