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Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for  many malignant and non-malignant hematological diseases. HSCT results have steadily improved over the past decades and its indications have become more refined over time.

In the 1970s, HSCT was reserved for patients less than 30 years of age who had an identical HLA sibling. Today, things have considerably changed and the number of transplants has increased significantly with the use of alternative graft sources such as unrelated adult donors, cord blood umbilical and, more recently, haploidentical family donors, allowing transplantation in patients who lack an identical HLA family donor, Likewise, the optimization of donor selection criteria, the improvement of post-transplant supportive care and the advent of conditioning regimens with reduced intensity have decreased transplant toxicity and broaden the indications and recipient’s age limits. Currently, more than 2 million patients have been treated with hematopoietic stem cell transplants worldwide.

A major advance was the possibility of using unrelated donors. Initially, international registers were set up for identifying adult voluntary donors HLA identical to the recipient. Then, the discovery that non-HLA-identical donors could also be used for transplantation dramatically increased the chances of finding a donor. The use of umbilical cord blood cells, collected at birth, has allowed for incompatible transplants to be performed because these cells, more immature, induce fewer immune reactions than adult cells. Another major advance was the possibility of using hematopoietic stem cells mobilized in the blood of family non-HLA-identical donors. Currently, more than 35 million unrelated adult donors and 783,000 cord blood units are listed and available worldwide. Now, we can actually say that finding a donor for a given patient is no longer a problem.

Results are getting better but there is still room for improvement, as post-transplant mortality remains high, primarily caused by transplant rejection, infectious complications, graft versus host disease (GVHD) and, in malignant disease, relapse.

Hematopoietic stem cell transplantation benefits from basic science research such as genomics, molecular biology, immunology, imaging, and artificial intelligence data analysis. New strategies to improve transplant outcomes are already being developed. They are based on gene therapy, the use of specific antibodies, new immunosuppressive drug or targeted therapies against tumor cell markers.

The most recent discoveries relate to gene therapy (for which the first results have already been published) to treat certain hereditary diseases like immune deficiencies and abnormalities in the red blood cell globin gene, such as thalassemia and sickle cell anemia. Two types of techniques are used in gene therapy; one is to use a lentiviral vector to transfer the corrective gene into the cell, the other is to correct the genetic abnormality by gene editing technique CRISPR-Cas9 genetic scissor, for which the scientists behind this revolutionary discovery were awarded the 2020 Nobel Prize in Medicine. These methods will cure a large number of hereditary diseases by using the patient’s own corrected cells and avoiding resorting to allogeneic cells.
Great advances have been made in immunotherapy. The production of monoclonal antibodies made targeting a number of tumor cells and infectious agents such as the EBV virus which causes infectious mononucleosis and certain lymphomas.

Cellular immunotherapy is rapidly expanding with the use of cells manipulated in the laboratory to react against tumor or infectious antigens. The most interesting method uses lymphocytes modified by the addition of a chimeric receptor recognizing specific targeted antigens. This is the case of lymphocytes called CAR-T which are modified lymphocytes to recognize and destroy leukemia and lymphoma B-cells. This treatment has resulted in spectacular disease remission in patients resistant to chemotherapy.
Other immunotherapy products are under study to treat a large number of leukemia and cancers. The same technologies can also be applied in the treatment of certain infectious diseases.

Molecular genomics made it possible to analyze the human genome and describe the mutations associated with cancers, which, in turn, has allowed for setting up targeted therapies to eradicate the malignant cells with precision. Several drugs have been designed to target specifically the gene products directly responsible of malignant transformation. These drugs more specific and less toxic will replace current more toxic chemotherapies. The most interesting methods use modified lymphocytes that recognize specifically the cancer cell by the addition of a chimeric receptor. A main example of this was the treatment of chronic myelogenous leukemia by inhibiting the effects of the bcr / abl translocation of the tumor cell. This treatment made it possible to cure this disease without a bone marrow transplant. Other targeted therapies are currently being tested.

All these results have been obtained through the interaction between basic science and translational research which has brought innovative products to market. Analysis of the results has been facilitated by the establishment of clinical research registries as well as artificial intelligence.
The 21st century has seen the emergence of new diagnostic and treatment methods, but it should not be forgotten that these results were possible due to decades of researchers’ hard work. The discoveries that have been made on stem cells have enabled us to develop our therapeutic arsenal and pave the way for the therapies of the future.