European researchers found that in pediatric patients going through hematopoietic stem cell transplant, prophylactic defibrotide seemed to reduce the incidence of hepatic veno-occlusive disease.

The leading cause of morbidity and death after hematopoietic stem-cell transplantation (HSCT) is hepatic veno-occlusive disease.

For many diseases like certain types of leukemias, stem cell transplant is the only viable option, but there are no current therapies approved to prevent hepatic veno-occlusive disease.

Early studies show that defibrotide may offer benefits as a prophylaxis for the treatment of veno-occlusive disease.

In a phase 3 trial of 28 university hospitals or academic medical centers, 356 patients younger than 18 years old were enrolled. According to a report published in The Lancet, by Selim Corbacioglu, MD, University of Regensbury in Germany and colleagues, in 30 days, patients were treated with defibrotide showed a 40% relative risk reduction for the incidence of veno-occlusive disease compared to the control group who did not receive any prophylaxis.

Adverse events were assessed through 180 days after the transplantation. In the first month after transplantation, significantly less patients on defibrotide got veno-occlusive disease. The patients treated with prophylactically had less organ and renal failure as well.

But between 100-180 days after transplantation, rates of mortality and serious adverse events between the groups were nearly the same.

Fatal adverse events were categorized into “neoplasms, malignant, and unspecified” (7% of patients treated with defibrotide and 8% of the patients in the control group) and “infections and infestations” (3% of patients treated with defibrotide and 6% of the patients in the control group).

Although the lack of an overall mortality benefit, the authors said that the study “will hopefully change practice in pediatric patients and might also provide an impetus to investigate treatment options for adult patients.”

Source:

Corbacioglu S, et al "Defibrotide for prophylaxis of hepatic veno-occlusive disease in pediatric hematopoietic stem cell transplantation: an open-label, phase III randomized controlled trial" Lancet 2012.

By coaxing healthy and diseased human bone marrow to become embryonic-like stem cells, a team of Wisconsin scientists has laid the groundwork for observing the onset of the blood cancer leukemia in the laboratory dish.

"This is the first successful reprogramming of blood cells obtained from a patient with leukemia," says University of Wisconsin-Madison stem cell researcher Igor Slukvin, who directed a study aimed at generating all-purpose stem cells from bone marrow and umbilical cord blood. "We were able to turn the diseased cells back into pluripotent stem cells. This is important because it provides a new model for the study of cancer cells."

Human bone marrow cells (left) were coaxed to become pluripotent, all-purpose stem cells (right) in a new study by a team led by University of Wisconsin-Madison stem cell researcher Igor Slukvin, a professor of pathology and laboratory medicine in the UW School of Medicine and Public Health. Slukvin's group turned banked healthy and diseased human bone marrow into blank-slate stem cells, which have potential use in therapy and could become a powerful laboratory model, as the new induced cells made from diseased marrow carry the same genetic mutations that cause the blood cancer chronic myeloid leukemia.

Photo: Jeff Miller

The research was reported today in the journal Blood by Slukvin and colleagues from the WiCell Research Institute and the Morgridge Institute for Research, private research centers in Madison.

Slukvin's group, using banked healthy and diseased bone marrow and cord blood, employed a technique developed in 2009 by Wisconsin stem cell pioneer James Thomson that sidesteps the problems posed by the genes and viral vectors used to induce mature cells to regress to a stem cell state.

The ability to pinpoint the very earliest stages of cancer is a major focus of biomedical science.

According to the new study, which was funded by the National Institutes of Health and The Charlotte Geyer Foundation, reprogramming blood cells to become induced stem cells is many times more efficient than the reprogramming of skin cells, which were the first mature cells to be guided back to an embryonic stem cell-like state.

The new work could open to science vast repositories of banked tissue, both healthy and diseased, such as bone marrow, the soft tissue in bones that helps make blood, and umbilical cord blood. The work could underpin insightful models capable of unmasking the cellular events that go awry and cause cancers such as leukemia, and could aid the development of new stem cell-based therapies, according to Slukvin.

Of particular note in the new study, says Slukvin, is the reprogramming of marrow cells from a patient with chronic myeloid leukemia, a cancer of the blood that kills about 1500 people a year in the United States. The disease, like all leukemias, starts in the cells that produce white blood cells in bone marrow.

According to Slukvin, the induced stem cells generated from the diseased tissue retain the exact same complex of genetic abnormalities found in the mature cancer cells. That means that when the induced cells are turned back into blood, scientists could, in theory, watch cancer develop from scratch as cells bearing cancer mutations become cancer stem cells.

"When we differentiate induced stem cells back to blood, we can identify the stages when the abnormality that leads to cancer manifests itself," Slukvin explains.

The ability to pinpoint the very earliest stages of cancer is a major focus of biomedical science.

"This is very important for developing new leukemia drugs," says Slukvin. "A major focus of leukemia research is to find ways to try and eliminate the most immature leukemia cells — cancer stem cells."

The work by Slukvin and his team may represent the first step in a new understanding of the cascade of events that results in blood diseases such as leukemia.

Employing the reprogramming technique developed by Thomson and his colleagues, Slukvin emphasizes, is important because it eliminates the exotic reprogramming genes, some of which are cancer-related genes, from the induced stem cell equation. In the case of chronic myeloid leukemia and other blood diseases, obtaining stem cells that do not have the genetic reprogramming factors is very important.

"When you use viruses (to ferry genes into a cell) you have chromosomal integration," the Wisconsin researcher notes. "Some of the reprogramming factors are oncogenes and would interfere with a study of chronic myeloid leukemia" whose abnormalities are also encoded on the chromosome.

In addition to Slukvin, an investigator at the Wisconsin National Primate Research Center (WNPRC) and an associate professor of pathology at the UW School of Medicine and Public Health, authors of the new study include Kejin Hu, Junying Yu and Kyung-Dal Choi of the WNPRC; Kran Suknuntha of the UW School of Medicine and Public Health; Shulan Tian, Ron Stewart and James A. Thomson of the Morgridge Institute for Research; and Karen Montgomery of the WiCell Research Institute.

Presentations Include Clinical Data from Two Phase One Trials of SB-728-T Confirming Mechanistic Proof of Concept and Expansion of ZFN-CCR5-Modified Cells in Presence of Actively Replicating Virus.

A small population of patients with chronic graft-versus-host disease demonstrated stable visual acuity, tear production and lissamine green staining, as well as a statistically insignificant improvement in dry eye over a 3-year period.