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Cord blood transplantation now a viable option for adult leukemia patients

Stem cell transplantation using umbilical cord blood is a standard treatment option for blood disorders in children, but not for adults, due to the difficulty of obtaining a sufficiently large dose of cells. To solve this problem, researchers from the University of Minnesota examined a new technique that combines two cord blood units from different donors for transplantation into adult or adolescent leukemia patients. Their study is to be published in the February 1, 2005, issue of Blood, the official journal of the American Society of Hematology.

Twenty-three patients with high-risk acute and chronic leukemias were studied for up to two and a half years. As is often the case, a suitably matched volunteer donor could not be found for these patients, and without an exact match, a transplant would likely be unsuccessful.

Cord blood is more tolerant of differences between patient and donor, making it possible to perform cord blood transplants without an exact match. Though a single cord blood unit with a satisfactory dose could not be found for these patients, senior study author John Wagner, M.D., Scientific Director of Clinical Research of the University of Minnesota's Blood and Marrow Transplantation Program and Stem Cell Institute, theorized that they could still have successful transplants if two partially-matched units were used for each patient.

"Currently, many adult leukemia patients are not eligible for an umbilical cord blood transplant due to the inability to find a single unit of blood with enough cells for transplantation. With this new technique of increasing the dose by combining two units, this procedure could be made available to thousands more patients and has the potential to save many lives," said Juliet N. Barker, M.B., B.S., Assistant Professor of Medicine at the University of Minnesota and co-author of the study.

While two patients with acute leukemia in relapse died from infection shortly after the transplant, in the remaining 21 patients, the transplanted stem cells completely incorporated themselves in the patient's body and began to produce normal, healthy cells. Disease-free survival was 57 percent at one year and, for those who received the transplant while their cancer was in remission, the success rate was even higher at 72 percent.

"The results of this study are heartening, but further investigation of this approach in larger clinical trials is needed to determine the full impact of this transplant procedure for adults and larger adolescents," said George Q. Daley, M.D., Ph.D., Associate Director of the Stem Cell/Developmental Biology research program at Children's Hospital Boston.

This work was supported in part by grants from the National Cancer Institute PO1-CA65493 and the Children's Cancer Research Fund.

The American Society of Hematology (hematology.orgis the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.

Blood, the official journal of the American Society of Hematology, is the most cited peer-reviewed publication in the field.

Blood is issued to Society members and other subscribers twice per month, available in print and online at http://www.bloodjournal.org.

Experimental drug shown to block mutant protein causing blood disease

Scientists at Dana-Farber Cancer Institute and Brigham and Women's Hospital have prolonged the lives of mice with a rare blood disorder by using an experimental drug that blocks signals promoting runaway growth of blood cells.

The researchers also tested the drug, PKC412, in a patient with the hard-to-treat disease, called Myeloproliferative Disease (MPD), and saw her symptoms improve.

PKC412, like the spotlight drug Gleevec, is a highly specific "targeted" drug that disables a switch in cancer cells that has become jammed in the "on" position because of a genetic mutation. The glitch allows a continuous stream of signals to prod blood cells into an uncontrolled frenzy of division and growth. The overproduction of white blood cells in MPD damages organs and generally turns into an acute leukemia that can be fatal.

The report appears in this week's Online Early Edition of the Proceedings of the National Academy of Sciences. Jing Chen, PhD, of Brigham and Women's, and Daniel J. DeAngelo, MD, PhD, of Dana-Farber, are the paper's co-first authors. D. Gary Gilliland, MD, PhD, a Howard Hughes Medical Institute investigator at Brigham and Women's Hospital, and Richard M. Stone, MD, of Dana-Farber are the senior authors. Other authors are from Dana-Farber, Brigham and Women's, Harvard Medical School, Emory University, and Novartis Pharma AG.

"The study shows the potential utility of drugs that block mutant tyrosine kinases, and that these drugs are opening more doors to treating cancers," explains Stone.

Tyrosine kinases are molecules that act as biological switches inside cells, regulating processes including cell division and growth. Abnormal kinases have been discovered to be major culprits in many forms of cancer. Because inhibitor drugs strike the abnormal kinases in cancer cells without harming normal tissue, they are associated with fewer side effects than standard cancer drugs.

In the study, mice with MPD that were treated with the oral compound PKC412 significantly outlived those given a placebo. When tested in a single patient, a 52-year-old woman with MPD, the drug reduced her dangerously high white blood cell count and shrank her enlarged spleen and lymph nodes. However, the disease wasn't cured and she underwent a bone-marrow transplant to treat the acute leukemia caused by her MPD.

PKC412 acts similarly to the pioneering drug Gleevec, one of the first drugs to treat cancers by shutting down abnormal kinase signal switches. Gleevec blocks uncontrolled growth signals in Chronic Myelogenous Leukemia and Gastrointestinal Stromal Tumor.

The Dana-Farber scientists have been testing PKC412 in patients with Acute Myeloid Leukemia, some cases of which are caused by a mutant on-off switch called FLT3. The drug specifically blocks abnormal FLT3 kinases.

MPD is caused by a different mutated kinase, FGFR1, which is inhibited by PKC412. The mutation occurs when two broken pieces of the chromosome that carries the FGFR1 gene join together abnormally.

The findings suggest, the authors write, that PKC412 may be effective in treating MPD, as well as other diseases and cancers where mutant FGFR1 is the culprit. These include human skeletal disorders such as Pfeiffer syndrome, which causes misshapen skull, face, fingers and toes, breast and pancreatic cancers, and brain tumors.

The research was supported by grants from the National Institutes of Health, the Leukemia and Lymphoma Society, and the Doris Duke Charitable Foundation.

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