Speakers tout latest research at ASH meeting

NMDP hosts symposium on advances in transplantation

Preceding the 42nd annual meeting of the American Society of Hematology (ASH), the National Marrow Donor Program^® (NMDP) sponsored five distinguished speakers to present talks at the NMDP-sponsored symposium "Technologies That Make Transplants Safer." The symposium, part of the ASH "Corporate Friday" program, took place on Friday, December 1, 2000, at the Moscone Convention Center in downtown San Francisco.

Advances in Transplantation Highlights

• Several factors have increased the number of potential stem cell donors available to patients searching the NMDP Registry:
• An increased number of potential donors are fully typed for HLA-A, -B, and -DR;
• 57% of the more than 4 million potential donors on the Registry have been fully typed; 95% of the transplants facilitated by the NMDP use donors from this pool of fully typed potential donors
• An increase in potential donors are from racial and ethnic minority groups
• Several aspects of the stem cell transplantation field have prevented many patients from enrolling in clinical trials:
• The lack of a cohesive network of transplant and referral centers for multi-center trials, resulting in transplant-related technologies that are never evaluated in randomized trials.
• Advances in stem cell transplantation have been slowed by the lack of standardized, objective, validated criteria for diagnosing and grading transplant complications, resulting in the reluctance of drug companies to sponsor clinical trials.
• Development of DNA-based techniques for high resolution tissue typing has led to a greater appreciation of the importance of matching for HLA class I and class II molecules.
• Preparative regimens are now being chosen based on the type of donor, the patient's malignancy, and the patient's age.
• New cell processing techniques, improvements in supportive care, and reductions in regimen-related toxicity have led to better patient outcomes.

Summary

Dr. Confer also presented data showing the increase in potential donors who are from racial and ethnic minority groups. "This accomplishment represents real progress in providing comparable access to stem cell transplants for patients of all racial and ethnic backgrounds," said Dr Confer.

Dr. Mary Horowitz, Scientific Director of the International Bone Marrow Transplant Registry (IBMTR), spoke on several aspects of the stem cell transplantation field that have prevented many patients from enrolling in clinical trials. A primary obstacle to enrolling patients in clinical trials, according to Dr. Horowitz, is the lack of a cohesive network of transplant and referral centers for multi-center trials. As a result, said Dr. Horowitz, most transplant-related technologies are never evaluated in randomized trials.

Dr. Horowitz also noted that advances in stem cell transplantation have been slowed by the lack of standardized, objective, validated criteria for diagnosing and grading transplant complications such as mucositis and graft-versus-host disease. In addition, transplant trials often involve high numbers of adverse events that are associated with the transplant procedure itself. As a result, said Dr. Horowitz, drug companies are often reluctant to sponsor clinical trials due to the high burden of reporting adverse events that are often unrelated to the therapy being evaluated. Dr. Horowitz called for better mechanisms for initiating and implementing multi-center trials so that promising single center Phase I and Phase II studies can be tested in large, definitive studies.

John Hansen, M.D., of the University of Washington, Seattle, and the Fred Hutchinson Cancer Research Center, spoke on overcoming barriers in the HLA system. Dr. Hansen noted that the development of DNA-based techniques for high resolution tissue typing has led to a greater appreciation of the importance of matching for HLA class I and class II molecules. As an example, Dr. Hansen cited research showing that allele-level typing for the class I HLA-A, B and C genes has led to the recognition that disparity for HLA-C is a risk factor for graft failure. Similar studies have led to improvements in the donor-selection process, said Dr. Hansen, which has led to better transplant outcomes.

Dr. Hansen also presented data from CML patients transplanted at the Fred Hutchinson Cancer Research Center showing no detectable survival difference between recipients of HLA-matched unrelated donor and HLA identical sibling grafts. These patients were matched for time from diagnosis to transplants, and age. In conclusion, Dr. Hansen stated that for selected patients, overall results for unrelated donor transplants can be comparable to the results achieved with HLA identical sibling donors, provided patients receive optimal supportive care.

James Gajewski, M.D., of the University of Texas M.D. Anderson Cancer Center, spoke on recent progress in reducing the toxicity of stem cell transplantation. A major advancement in stem cell transplantation in the 1990s was the realization that one pre-transplant regimen is not appropriate for all patients, according to Dr. Gajewski. "Regimens are now being chosen based on the type of donor, the patient's malignancy, and the patient's age."

Especially promising for older patients in their 60s and 70s are transplants using non-myeloablative preparative regimens. In these transplants, the purpose of the preparative regimen has shifted from being both tumorcidal and immunosuppressive to simply being immunosuppressive to allow engraftment to take place, said Dr Gajewski, adding that a graft-versus-malignancy effect controls the patient's cancer. Dr. Gajewski also highlighted several other advances in stem cell transplantation that have led to better patient outcomes, including new cell processing techniques, improvements in supportive care, and reductions in regimen-related toxicity.

John E. Hearst, Ph.D., D.Sc., Professor Emeritus of the University of California - Berkeley, spoke on some of the nucleic acid chemistry that forms the basis of many chemotherapy drugs in use today. Dr. Hearst recounted how difficult it has been for biochemists to understand DNA replication, a process involving the duplication of a molecule that is several tens of centimeters long, yet is normally twisted into a volume of cubic microns. Dr. Hearst demonstrated the current model that explains how such a long molecule can undergo chromosome segregation during anaphase without becoming entangled in itself. The answer is the "growing fork model" of DNA replication, which supposes that the DNA is "kinked" at successive lengths of about 100 base pairs by a change in the structure of chromatin fibers.

Understanding the process by which DNA replicates itself and repairs itself is key to designing chemical reagents to disrupt these processes, said Dr. Hearst. The most effective chemotherapy drugs are likely to come from chemical families such as the bifunctional mustards, cisplatins, and psoralens, as these are the cross-linking reagents that are the most efficient at disrupting DNA replication.