In this issue of Blood, Grewal and colleagues from the University of Minnesota (page 1147) report on the first successful matched sibling donor transplantation in which the sibling donor was created by preimplantation genetic diagnosis and in vitro fertilization (PGD/IVF). A 3-year-old child with Fanconi anemia (FA) presented to the University of Minnesota with marrow failure, but no matched sibling donor was available. The family was informed that a matched sibling donor transplantation results in about an 85% chance of success, but an unrelated donor transplantation was much less likely to be successful, with registry data suggesting about a 20% to 30% chance of success. Since the child was stable and not imminently in need of a transplant, the family was offered the option of PGD/IVF to allow selection of an embryo for implantation who would not only not have FA, but would also be a perfect HLA match for their child with FA. The family accepted the challenge, and 4 years later, after 5 cycles of IVF/PGD and an expense of perhaps $75 000 to $100 000, the mother became pregnant and delivered a healthy child. At delivery, the cord blood was collected and stored and then used a month later for a matched sibling donor transplantation, which resulted in the cure of the sibling's FA, which by then had progressed to myelodysplasia (MDS). The recipient is healthy with full donor engraftment, normal blood counts, and no MDS more than 2 years later. The donor is a healthy and loved toddler. There were 2 other families that also took the same route, but neither was successful.
This amazing story brings up many points. First, it is indeed possible to create a sibling who is an HLA match and also does not have the genetic disease of the sibling. But the process may take a long time, is expensive, and may not be covered by insurance. The ordeal will be hard on the family both physically and psychologically, and in the end may not result in a successful pregnancy. The process requires very close collaboration between the transplant team, the family, the obstetrician, the IVF specialist, the PGD lab, and the geneticist. For the journey to be successful, the gene mutations must be identified and single-cell polymerase chain reaction (PCR) tests must be available or newly created to test for the gene mutations and the HLA types. The child in need of the transplant must not be in imminent need, since the process requires a minimum of one year and sometimes several years. There must be clear evidence that the outcome of a matched sibling donor transplantation is considerably better than that of an unrelated donor transplantation. The positive side of the equation is that the recipient will have a better chance of survival with a matched sibling donor transplantation. Also, it is reasonable for insurance companies to cover this technology in selected cases because of the improved chance of survival and because the difference in cost between an unrelated donor and a matched sibling donor transplantation more than covers the cost of the PGD/IVF expenses.
For PGD/IVF for this purpose to become an accepted therapy, it is important that many issues be addressed. Who can be offered this therapy and in what circumstances? How will families be screened to ensure their motives are pure? Who will pay the bill? How does society ensure there is no misuse of this technology? The authors address these issues and many more. A new doorway has been opened. We need to be sure our journey through this open door takes us down the right path.