Clincal Trial Validates Stem Cell-Based Treatments of Sickle Cell Disease in Adults

Santosh Saraf and his colleagues at the University of Illinois have used a low-dose irradiation/alemtuzumab plus stem cell transplant procedure to cure patients of sickle-cell disease. 12 adult patients have been cured of sickle-cell disease by means of a stem cell transplantation from a healthy, tissue-matched donor.

This new procedure obviates the need for chemotherapy to prepare the patient to receive transplanted cells and offers the possibility of curing tens of thousands of adults from sickle-cell disease.

Sickle cell disease is an inherited disease that primarily affects African-Americans born in the United States. The genetic lesion occurs in the beta-globin gene that causes hemoglobin molecules to assemble into filaments under low-oxygen conditions. These hemoglobin filaments deform red blood cells and cause them to plug small capillaries in tissues, causing severe pain, strokes and even death.

Fortunately, a bone marrow transplant from a healthy donor can cure sickle-cell disease, but few adults undergo such a procedure because the chemotherapeutic agents that are given to destroy the patient’s bone marrow leaves from susceptible to diseases, unable to make their own blood cells, and very weak and sick.

Fortunately, a gentler procedure that only partially ablate the patient’s bone marrow was developed at the National Institutes of Health ()NIH) in Bethesda, Maryland. Transplant physicians there have treated 30 patients, with an 87% success rate.

In the Phase I/II clinical trial at the University of Illinois, 92% of the patients treated with this gentler procedure that was developed at the NIH.

Approximately 90% of the 450 patients who received stem cells transplants for sickle-cell disease have been children. However, chemotherapy has been considered too risky for adult patients who are often weakened far more than children by it.

Adult sickle-cell patients live an average of 50 years with a combinations of blood transfusions and pain medicines to manage the pain crisis. However, their quality of life can be quite low. Now, with this chemotherapy-free procedure, adults with sickle-cell disease can be cured of their disease within one month of their transplant. They can even go back to work or school and operate in a pain-free fashion.

In the new procedure, patients receive immunosuppressive drugs just before the transplant, with a very low dose of whole body radiation. Alemtuzumab (Campath, Lemtrada) is a monoclonal antibody that binds to the CD52 glycoprotein on the surfaces of lymphocytes and elicits their destruction, but not the hematopoietic stem cells that gives rise to them.  Next, donor cells from a healthy a tissue-matched sibling or donor are transfused into the patient. Stem cells from the donor home to the bone marrow and produce healthy, new blood cells in large quantities. Patients must continue to take immunosuppressive drugs for at least a year.

In the University of Illinois trial, 13 patients between the ages of 17-40 were given transplants from the blood of a healthy, tissue-matched sibling. Donors must be tested for human leukocyte antigen (HLA) markers on the surfaces of cells. Ten different HLA markers must match between the donor and the recipient for the transplant to have the best chance of evading rejection. Physicians have transplanted two patients with good HLA matches, to their donor, but had a different blood type than the donor. In many cases, the sickle cells cannot be found in the blood after the transplant.

In all 13 patients, the transplanted cells successfully engrafted into the bone marrow of the patients, but one patient failed to follow the post-transplant therapy regimen and reverted to the original sickle-cell condition.

One year after the transplantation, the 12 successfully transplanted patients had normal hemoglobin concentrations in their blood and better cardiopulmonary function. They also reported significantly less pain and improved health and vitality,

For of the patients were able to stop post-transplantation immunotherapy, without transplant rejection or other complications.

“Adults with sickle-cell disease can be cured with chemotherapy – the main barrier that has stood in the way for so long,” said Damiano Rondelli, Professor of Medicine and Director of the Stem Cell Transplantation Program at the University of Illinois. “Our data provide more support that this therapy is safe and effective and prevents patients from living shortened lives, condemned to pain and progressive complications.”

These data were published in the journal Biology of Blood and Marrow Transplantation, 2015; DOI 10.1016/j.bbmt.2015.08.036.

Regulating Gene Expression Pushes Tumors into Remission

A study published online by the journal Science Translational Medicine discusses a new experimental treatment for a rare, deadly leukemia (blood cancer) that can send the disease into remission even in those patients for whom the standard therapy has failed. Such a treatment can buy patients more time to have a stem cell transplant that could save their lives. This study was only a small pilot study, but these findings are potentially revolutionary.

“It was unbelievable, really, seeing a patient who had already failed Campath [the drug typically used to treat the disease] literally going back into remission,” said Thomas P. Loughran Jr., MD, the director of the University of Virginia Cancer Center, who also served as one of the lead researchers of this study. “We were able to get every single patient back into remission.”

This new approach for battling T-cell prolymphocytic leukemia combines immunotherapy, which boosts the body’s immune system, with the manipulation of gene activity. Such a strategy might cast the mold for treatments for not only T-cell prolymphocytic leukemia, but other cancers as well. “There’s been a revolution in the last few years seeing success with immunotherapy, and people speculated that perhaps if you combined epigenetic and immunotherapy, that might be even more spectacular,” Loughran said. “This is proof of principle that this might be true.”

The pilot study, led by Loughran at UVA and Elliot Epner, MD, at Pennsylvania State University College of Medicine, looked at eight patients with T-cell prolymphocytic leukemia, which is an aggressive cancer that is extremely difficult to treat. T-cell prolymphocytic leukemia is also extremely rare and appears mostly in older men.

Cancer cells in patients with T-cell prolymphocytic leukemia have a cell-surface protein called CD52. By using an antibody to CD52, in the form of a drug called alemtuzumab (a monoclonal antibody to CD52), some patients can be driven into complete remission that lasts, for the most part, between 6-12 months. Alemtuzumab binds to CD52 and directs white blood cells to destroy them (see here).  However, if patients do not receive a bone marrow transplant, the cancer will come back and the cells will not be as sensitive to alemtuzumab. The reason for this resistance is that the cancer cells have down-regulated the expression of CD52. In this reports, patients were given drugs that prevent genes from being silenced (known as histone deacetylase inhibitors). The data from this study shows that the co-administration of epigenetic agents can overcome resistance to alemtuzumab, since the histone deacetylase inhibitors prevented the cancer cells from down-regulating their CD-52 genes.


Although this experimental approach did not cure the patients, it did send them all into remission. Furthermore, it works as well as predicted; patients could be re-treated and receive the same benefit each time. These treatments gave patients vital time as they looked for a suitable bone marrow/stem cell donor. Patients with T-cell prolymphocytic leukemia must have disease that is in remission in order to first receive the transplant.

There are limitations to this approach. Mounting toxicity limits how many times the treatment can be administered. Secondly, the suppression of the immune system can lead to infections and other complications. But the treatment has made a significant difference for all those patients who participated in this study. One patient was expected to live only four months but survived 34. Three others were still alive at the time the researchers were compiling the trial results.

The drugs used in the treatment are already commercially available, meaning doctors could, in theory, administer the treatment without further testing. Loughran, however, believes there needs to be additional study, hopefully in larger trials, but the rarity of the disease makes recruiting subjects difficult. Loughran encourages patients with the disease to consider seeking treatment at UVA. “We’d be very glad to see them here, if they want to come see us,” he said.