The MDS Beacon™

Treatment with treosulfan and fludarabine was effective and caused few negative side effects in myelodysplastic syndromes patients receiving donor stem cell transplants, according to a recent clinical trial conducted by researchers in Washington and Oregon.

By the end of the trial, all surviving patients successfully achieved complete engraftment of the donor stem cells, meaning that the donor stem cells began producing healthy blood cells and none of the patient’s stem cells remained.  Overall, the treatment was particularly effective in patients categorized as low- or standard-risk based on their genetics.

Only 15 percent of the MDS patients relapsed within two years of their transplant, regardless of their risk category.

“I think this is a very promising regimen to treat [MDS]”, said Dr. Eneida Nemecek, lead author of the study, in an email to The MDS Beacon.

The researchers concluded that due to relatively low side effects, the treosulfan/fludarabine conditioning regimen could be combined with other conditioning regimens.

“For patients at higher risk disease, adding something to the regimen (low dose radiation, other chemotherapy or targeting agents such as radiolabeled antibodies) may be of benefit,” said Dr. Nemecek. She added, “the trick is not to add so much that we end up encountering too much toxicity.”

Conditioning treatments are given to MDS patients in order to destroy their defective stem cells so that donor stem cells can engraft properly.  Stem cell transplants are currently the only curative treatment for MDS.

However, the intensity and toxicity of conditioning treatments usually come with many negative side effects.  Lower intensity conditioning treatments produce fewer side effects and treatment-related deaths, but also come with higher rates of relapse and graft failure.

Therefore, researchers are trying to find conditioning regimens with good engraftment results and overall survival without many side effects.

In this study, the researchers investigated treosulfan and fludarabine (Fludara) for their potential use as conditioning treatments. Preliminary European studies on treosulfan conditioning showed improved survival and fewer treatment-related deaths. Treosulfan is currently not approved in the United States. However, it is approved in Europe under the brand name Ovastat for the treatment of ovarian cancer.

The researchers recruited 60 patients (44 with acute myelogenous leukemia, three with acute lymphoblastic leukemia, and 13 with MDS), with a median age of 46.  None of the patients were in poor overall health, and 12 patients had high-risk genetic mutations in the bone marrow. Of the 60 patients participating in the trial, 30 received donations from siblings and 30 from unrelated donors. 

The patients received conditioning treatment over a period of four days.  They were given treosulfan and fludarabine for the first two days, then treosulfan alone for the next two days.  They then had two days with no further conditioning before their transplant procedures.

The researchers observed patients immediately after their transplants and conducted follow-up exams after recovery. 

They found all patients engrafted. The donated white blood cells started to reproduce at a median of 18 days, and the donated platelets started to reproduce at a median of 16 days after transplantation.

One hundred days after the transplant, 5 percent of patients had died of causes that were not related to relapse. The estimated death rate not related to relapse was 8.3 percent at two years after the transplant.

The researchers estimated that for the study population, which included MDS patients as well as other leukemia patients, 65 percent would survive at least two years.  Relapse-free survival was estimated to be 58 percent at two years. Patients with intermediate-risk disease had a higher probability of relapse-free survival (88 percent) than patients with high-risk disease (39 percent).

Genetic abnormalities, donor stem cells, overall disease risk category, and the presence of other diseases all affected patient prognosis. 

 Common side effects of the treosulfan/fludarabine conditioning treatment included skin rashes and inflammation of the digestive tract. 

Most patients also suffered an immune system reaction from the donated bone marrow called graft-versus-host disease.  Fifty-five percent of patients had immediate reactions, and 65 percent had chronic reactions. In 68 percent of patients, chronic graft-versus-host disease was resolved at a median of 18 months after stem cell transplantation.

For more information, please see the study in Biology of Blood and Marrow Transplantation (abstract).