Umbilical Cord Blood and Bone Marrow Transplants in Myelodysplastic Syndrome

Myelodysplasia syndrome (MDS) killed my mother. Therefore, this paper caught my eye.

This paper describes a multicenter study from Argentina that examined children with MDS. MDS affects the blood cell-producing stem cells in the bone marrow so that these cells make immature red blood cells that do not properly carry oxygen to tissues. The rogue stem cells produce droves and droves of these immature cells that overpopulate the bone marrow and crowd out the normal bone marrow stem cells. Patients with MDS suffer shortness of breath, weakness and fatigue, mental lapses, and other symptoms of anemia.  They also must rely on blood transfusions in order to keep them alive. Bone marrow transplants or umbilical cord transplants can cure MDS patients.

In this study, Ana Basquiera, from the Hospital Privado Centro Médico de Córdoba, Argentina, and her colleagues evaluated the overall survival, disease-free survival (DFS), non-relapse mortality (NRM) and relapse incidence in MDS children who underwent bone marrow and umbilical cord transplants. These children received these transplants in six different clinical throughout Argentina. All in all, 54 transplants were conducted in 52 patients. The mean age of these patients was 9 years old (range: 2–19), and 35 of the patients were males.

Several different types of MDS were seen in these patients, but all of them were not treatable by other means. Because MDS often precedes leukemia, seven (13%) patients at the time of the transplant transformed to acute myeloid leukemia (AML) and the diagnosis of two other patients also worsened.

All patients had their own bone marrow wiped out by means of a “conditioning regimen.” These are drugs that destroy the bone marrow stem cells of the patient and leave them without the means of make their own red blood cells or immune cells. Patients must then receive high doses of antibiotics and anti-fungal drugs while their bone marrow is repopulated. As you can guess, this is a nasty, dangerous procedure.

Of these patients, 63% received bone marrow stem cells, 26% stem cells from peripheral blood, and 11% umbilical cord blood. Five-year disease-free survival and overall survival were 50% and 55% respectively; and for patients with juvenile myelomonocytic leukemia, 57% and 67% respectively.

Cumulative incidence of non-relapse mortality and relapse were 27% and 21% respectively. Statistical analyses of the data from these treatments showed that patients who had received umbilical cord blood (HR 4.07; P = 0.025) and were younger than nine years old tended to have a lower overall survival rate. Also, younger patients who experienced graft-versus-host disease (GVHD), in which the engrafted immune cells begin to attack the tissues of the patient, had a higher rate of non-relapse mortality (no real surprise there).

Thus, more than half of the patients achieved long-term overall survival. The mortality and relapse rates were rather high, however, and it is possible that less toxic conditioning regimens or more intensive prevention of GVHD could lead to better results in some children. Until such procedures are make available, such mortality rates will probably remain high, even though the procedure does potentially cure the patients of MDS.  Thus this remains a “high risk, big pay-off” procedure.

This was published in Pediatric Blood and Cancer.

Stem Cells to Make Red Blood Cells and Platelets in Culture

A collaborative study between Boston University School of Public Health and researchers at Boston Medical Center has used induced pluripotent stem cells to make unlimited numbers of human red blood cells and platelets in culture.

This finding could potentially reduce the need for blood donations to treat patients who require blood transfusions. Such research could also help researchers examine fresh and new therapeutic targets in order to treat blood diseases such a sickle-cell anemia.

The lead scientist on this project was George Murphy, assistant professor of medicine at Boston University School of Medicine and co-director of the Center for Regenerative Medicine at Boston University. Murphy’s main collaborator was David Sherr, professor of environmental health at Boston University School of Medicine and the Boston University School of Public Health.

Induced pluripotent stem cells or iPSCs are made from adult cells by applying genetic engineering technology to the adult cells that introduces genes into them. The introduction of four specific genes de-differentiates the adult cells into pluripotent stem cells that can, potentially, differentiate into any adult cell type. This makes iPSCs powerful tools for research and potential therapeutic agents for regenerative medicine.

In this study, Murphy and others used iPSCs from the CreM iPS Cell Bank and exposed them to a battery of different growth factors in order to push them to differentiate into different adult cell types. They were looking for the precise cocktail to differentiate iPSCs into red blood cells, since they wanted to further study red blood cell development in detail.

One group of compounds given to the set of iPSCs were molecules that activate “aryl hydrocarbon” receptors. Aryl hydrocarbon receptors (AHRs) play important roles in the expansion of hematopoietic stem cells, which make blood cells, since antagonism of AHRs promotes expansion of hematopoietic stem cells (see AE Boitano et al.,Science 10 September 2010: Vol. 329 no. 5997 pp. 1345-1348). In this case, however, Murphy and his colleagues observed a dramatic increase in the production of functional red blood cells and platelets in a short period of time. THis suggests that the ARH is important for normal blood cell development.

Aryl Hydrocarbon Receptor
Aryl Hydrocarbon Receptor

“This finding has enabled us to overcome a major hurdle in terms of being able to produce enough of these cells to have a potential therapeutic impact both in the lab and, down the line, in patients,” said Murphy. “Additionally, our work suggests that AHR has a very important biological function in how blood cells form in the body.”

“Patient-specific red blood cells and platelets derived from iPSC cells, which would solve problems related to immunogenicity and contamination, could potentially be used therapeutically and decrease the anticipated shortage and the need for blood donation,” added Murphy.

iPS-derived cells have tremendous potential as model systems in which scientists can test and develop new treatments for disease, given that such diseases can be constructed in the laboratory. These iPSC-derived red blood cells could be used by malaria researchers, and IPSC-derived platelets could be used to explore cardiovascular disease and treatments for blood clotting disorders.

Because my mother died from myelodysplasia, this finding has some personal interest to me. Mom had a difficult blood type to match, since she had the Bombay blood type (H). Finding blood for her was a major tour de force, and as she received blood that was less and less well matched to her body, she suffered the ravages of poorly matched blood. A treatment of red blood cells made from IPSCs derived from her own cells might have extended her life and even improved her quality of life in her later years.

I look forward to this research eventually culminating in clinical trials.