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Blood and Marrow Transplantation
Research
The physicians at Children’s BMT program are constantly striving to improve cellular therapies for treatment of childhood cancer and blood diseases. A number of studies are underway looking at treatment methods that will make marrow and cord blood transplants kinder, gentler and safer. Their ultimate goals are to reduce the complication rate and improve quality of life for children undergoing this procedure.
Meet the Researchers
- Rakesh K. Goyal, MD, director of Blood and Marrow Transplantation
- Lakshmanan Krishnamurti, MD, director of the Comprehensive Hemoglobinopathy Program
- Peter Shaw, MD
Research Interests
- Graft-Versus-Host Disease
- Ex-vivo Stem Cell Expansion
- BMT for Sickle Cell Disease and Thalassemia
- Clinical Trials
Graft-versus-Host Disease
Dr. Rakesh Goyal’s clinical research is focused on understanding the relationship between individual genetic variability and the outcome of transplant therapy. He is studying ways we may be able to predict the risk of serious complications, such as graft-versus-host disease, and how that might lead to individualized therapy.
Certain gene products called cytokines play an important role in GVHD, rejection and other complications associated with BMT. Some cytokines cause more inflammation and damage to body tissues, leading to more severe GVHD; whereas others may suppress local inflammation and tissue damage, thus helping to prevent rejection. Individuals differ in their capacity to make specific cytokines. These differences between "high" and "low" producers of cytokine molecules may not matter as much in healthy children. However, Dr. Goyal’s group speculates that individual variation in making cytokines and other key regulatory molecules may influence a child’s outcome after transplantation. They are investigating this theory on children undergoing allogeneic transplantation in an international multi-institutional study.
Ex-vivo Stem Cell Expansion
The use of umbilical cord blood in transplant is another area of focus at Children’s Hospital of Pittsburgh. Cord blood is used the same way bone marrow is in transplant, except that a perfect match is not necessary for cord blood transplantation to attain the same positive outcome.
Dr. Peter Shaw’s area of research is ex-vivo stem cell expansion. He is manipulating cord blood stem cells in an attempt to shorten the time it takes for platelets in cord blood to find a home in the recipient’s marrow. Delayed platelet engraftment is a significant problem in all stem cell transplant recipients, but especially in UCB transplants. It takes 55 to 75 days for platelets to rejuvenate after cord blood transplant, compared to about 25 days after BMT. Dr. Shaw’s hope is that by giving an enriched cord blood product to patients their platelets will recover more quickly after transplant.
Dr. Shaw
is addressing
the challenge
through ex-vivo
expansion
of UCB stem
cells in two
ways:
1.) By incubating
them in a
specialized
cytokine "cocktail"
which drives
the stem cells
toward megakaryocytic
(early platelet)
lineage
2.) Through
genetically
"rewiring"
stem cells
by inserting
genes that
drive platelet
development
and stem cell
expansion
For
more information
about this
research,
please see:
Shaw PH, Olszewski
M, Kletzel
M: Expansion
of megakaryocyte
precursors
and stem cells
from umbilical
cord blood
CD34+ cells
in collagen
and liquid
culture media.
Jnl of Hematotherapy
and Stem Cell
Research,
10:391-403,
2001.
Shaw PH, Gilligan D, Wang X, Thall PJ, Corey SJ: Ex vivo explansion of megakaryocyte precursors from umbilical cord blood CD34+ cells in a closed liquid culture system. Biol Blood Marrow Transplant, 2003:9(3):151-156.
BMT for Sickle Cell Disease and Thalassemia
Dr. Lakshmanan Krishnamurti’s clinical research is focused on developing newer, gentler types of bone marrow transplantation for patients with inherited blood disorders, such as sickle cell disease and Thalassemia. Most often, stem cell transplantation is used to treat cancer. However, BMT is the only procedure that can cure sickle cell disease, a blood disorder affecting more than 50,000 Americans.
Children with sickle cell disease have crescent-shaped, sticky, rigid red blood cells that obstruct blood flow and decrease the amount of oxygen reaching their organs, which causes frequent pain crises. Eventual outcomes include organ shutdown and, on average, a 30-year loss of life expectancy. Approximately 60 BMTs for sickle cell disease have been performed in the United States in the last 10 years because the stringent criteria and stigma of BMT--that it is an intensive treatment requiring weeks of hospitalization--kept patients away.
To increase the number of sickle cell patients undergoing BMT, the procedure had to be made safer and less toxic. Researchers, such as Dr. Krishnamurti, have learned that BMT becomes less toxic when large doses of immunosuppressive medications are given before transplant, instead of high doses of chemotherapy. This reduced intensity conditioning reduces many of the risks and side effects associated with BMT.
Dr. Krishnamurti performed the first successful BMT using such a reduced intensity conditioning regimen on an 8-year old girl with sickle cell disease. Ultimately, it is hoped that such reduced intensity conditioning regimens will make BMT available to many more patients with sickle cell disease and Thalassemia.
For
more information
about this
research,
please see:
Krishnamurti
L, Blazar
BR, Wagner
JE: Bone marrow
transplantation
without myeloablation
in a patient
with sickle
cell disease.
The New England
Journal of
Medicine,
344(1):68,
2001.
Clinical Trials
| Protocol | Type of Trial | Sponsorship* |
Reduced Intensity Conditioning Hematopoietic Cell Transplantation for Pediatric Patients with Hematologic Malignancies at High Risk for Transplant Related Mortality with Standard Transplantation; A Multi-center Trial for the Pediatric Blood and Marrow Transplant Consortium (PBMTC) |
Treatment |
PBMTC |
A Pilot Study of Allogeneic Hematopoietic Stem Cell Transplant for Patients With High Risk Hemoglobinopathy Using a Non-Myeloablative Preparative Regimen to Achieve Stable Mixed Chimerism |
Treatment |
Institutional |
Rapamycin for Immunosuppression and B Cell Modulation Post Stem Cell Transplant for Acute Lymphoblastic leukemia |
Treatment |
Limited Institution Pilot |
ANBL0032, Phase III Randomized Study of Chimeric Anti-GD2 in High Risk Neuroblastoma Following Myeloablative Therapy and Autologous Stem Cell Rescue |
Treatment |
COG |
Initial Systemic Treatment of Acute GVHD: A Phase II Randomized Trial Evaluation Etancercept, Mycophenolate Mofetil (MMF), Denieukin Difitox (Ontak) and Pentostatin in Addition to Corticosteriods |
Treatment |
BMT CTN |
National Marrow Donor Program (NMDP) Recipient Consent for Participation in Research Database and/or Research Sample Respository |
Biology |
NMDP |
Defibrotide for the Treatment of Venoocclusive Disease of the Liver |
Treatment |
Institutional |
GVH0112, Cytokine Gene Polymorphisms in Pediatric Patients Receiving Tacrolimus or Cyclosporin for Graft-versus-Host Disease Prophylaxis |
Biology |
PBMTC |
PBMTC051: Soluble Tumor Necrosis Factor Receptor Embrel (Etanercept) for the Treatment of Acute Non-Infectious Pulmonary Dysfunction (Idiopathic Pneumonia Syndrome following Allogeneic Stem Cell Transplantation |
Treatment |
COG |
For more information about trial participation, please call 412-692-6740.
* Sponsorship
COG = Children’s Oncology Group
NMDP = National Marrow Donor Program
PBMTC = Pediatric Blood & Marrow Transplant Consortium
BMT CTN = Blood and Marrow Transplant Clinical Trials Network
