One of the major challenges in the past 40 years of stem cell transplantation has been donor availability. Matched sibling donors have always been the gold standard for successful allogeneic transplantation, but in the United States — due to small contemporary family size — the likelihood of having an HLA-matched sibling is less than 30%.
So what can we do with the 70% of patients who do not have family member donors? The first major innovation was the establishment of international registries to provide volunteer unrelated donors. Initially, volunteer donor availability outstripped our ability to do precise HLA typing, and transplant outcomes with unrelated donors were dismal. The introduction of high-resolution molecular HLA typing was a huge step forward, allowing the outcomes of matched unrelated donor transplantation to closely approach the outcomes for sibling transplantation.
Unfortunately, the registries are largely composed of people of western European descent, so — despite the 22 million registered donors — matches can still be difficult to obtain for patients from other ethnic groups. While there have been successful efforts to increase minority participation in the registries, donor availability is still limited by the remarkable heterogeneity of HLA.
The use of partially mismatched related and unrelated donors is an acceptable compromise, but the use of single-antigen mismatched donors is associated with more risk and only marginally increases the donor pool. We can now interrogate the DNA sequence of the HLA molecules, which allows us to choose mismatched donors that are "permissive," i.e. they function as if they are matched since the specific HLA disparity is not recognized by T cells. This is a step forward, but there are still large numbers of patients needing donors for whom no registry donor is available.
Within the past 10 years, we have embraced the use of two additional donor sources that now makes the person without a potential donor a rarity: umbilical cord blood cells and haploidentical donors.
The adoption of umbilical cord blood stem cells allowed the crossing of HLA barriers by virtue of the low numbers of T cells in cord blood and their complete immunologic immaturity. Cord blood transplants are limited by slow count recovery and slow immunologic reconstitution. We here in the Dana-Farber/Brigham and Women's Cancer Center Adult Stem Cell Transplantation Program and others are addressing this limitation in several ways.
Double cord blood transplantation is normally used in adults in the United States to provide an extra increment of stem cells. This is quite expensive and does nothing to improve immune reconstitution. Based on work done in collaboration with our colleagues at Dana-Farber/Boston Children's Cancer and Blood Disorders Center, we are investigating the use of dimeric prostaglandin E2 as a way of increasing the viability and marrow homing capacity of cord blood stem cells. Moreover, ex vivo expansion of these cells has shown promise in accelerating count recovery.
Haploidentical transplantation has finally come into its own. Haploidentical transplants use donors that are mismatched at fully half of the HLA complex. Fifty percent of siblings are likely to be haploidentical, and children and parents are obligatory haploidentical donors. For years, using haploidentical donors was associated with very high rates of graft-versus-host disease and graft rejection. These limitations of haploidentical transplantation were the most recalcitrant problems we faced in the stem cell transplant field. However, in the past few years we have made substantial headway, and now these transplants are done frequently with outcomes comparable to umbilical cord blood and matched unrelated donors. It is now the rare individual for whom no donor can be found.
One of our major research endeavors currently is a randomized trial of umbilical cord blood versus haploidentical donors for patients lacking a sibling or fully matched adult unrelated donor. This study is designed to determine whether one source of stem cells has an advantage in outcome or cost.
For those of us who have been doing transplantation for a long time, it is amazing that this study was even conceived, let alone that it is open and accruing well. This is not to say everything is perfect: we are still faced with the challenges of graft-versus-host disease, opportunistic infections, and disease relapse. However, increasingly these barriers to successful transplantation are falling, too, as our biologic sophistication improves.
— Joseph Antin, MD, Chief and Program Director, Adult Stem Cell Transplantation Program