The concept of allogeneic HSCT is pivoted on compatibility of HLA antigens between the patient and the donor which are inherited from parents and passed on to the off-springs. Whilst 20% of the patients might find an HLA-compatible donor from within the family, the majority of such patients are left without one. This led to the establishment of Volunteer Unrelated Donor Registries across the globe. Rapid expansion of such registries enabled 60-80% of patients of Caucasian descent in finding a suitably HLA-matched donor. On the other hand, unrelated cord blood (UCB) units emerged as an alternate option with less stringent HLA-matching.
The last 5 decades have seen enormous development in the field of immunogenetics. High-resolution HLA typing on retrospective cohorts have demonstrated the need for very stringent HLA matching at all relevant HLA antigens. These developments have reduced the chance of finding an optimally matched donor, particularly for the non-Caucasian population. Similar retrospective analyses on mismatched UCB transplantation have also emphasized the need for more stringent HLA matching to reduce mortality. This is perhaps a typical example of how scientific precision aimed at improving outcomes might make making enable use of unrelated source of stem cells, either marrow or cord, have led researchers to explore permissiveness of mismatches. Amidst this quest for a perfect match with a stranger, some of us have stopped to look again within the family. The natural law of tolerance led to the exploration of HLA haplotype matched first degree relatives as possible donors. Through either graft manipulation or pharmacological interventions, the outcomes following HSCT from haploidentical family donors for haematological malignancies do not seem to be worse than matched related or unrelated donors. Yet, the exuberance of early success and ease of conducting such transplants with inexpensive pharmacological interventions have led to widespread use of haploidentical HSCT without the checks and balances. We have demonstrated over the last 6 years how the outcome in malignant disorders could be enhanced in the setting of haploidentical HSCT. At the same time, we have brought to the fore the differing dynamics in non-malignant disorders and in children undergoing the same procedure for haploidentical HSCT. The night is young and the day is long; our quest for the perfect match is far from over.