Brenda M. Sandmaier
M.D., University of Alberta.
B.Sc., University of Alberta, Genetics.
Stem cell engraftment in MHC-matched and mismatched transplants: development of nonmyeloablative conditioning regimens
Our primary goal is to develop conditioning regimens that have minimal toxicity and, thus, allow us to extend the benefit of stem cell transplants to a greater number of patients. Towards that end, we are using a preclinical model and have extended our findings to patients in clinical studies.
The long-term objective of the development of nonmyeloablative conditioning regimens is to extend the application of stem cell transplants to use in older patients and patients with nonmalignant diseases, in addition to patients with malignancies, by developing less toxic conditioning regimens that permit engraftment and prevent graft-versus-host disease (GVHD). To address this goal, nonmyeloablative conditioning regimens for hematopoietic allografts are being studied in a preclinical model. Data indicate that MAbs directed towards CD3/TCR facilitate establishment of donor chimerism in preclinical MHC-identical related transplants in a low dose radiation model. In MHC-haploidentical transplants, data indicate that the anti-CD44 MAb S5 establishes donor engraftment in the low dose radiation model when given with standard immunosuppression.
Attempts to increase the dose of chemoradiotherapy to prevent relapse after transplant have been limited by toxicity to normal organs. Previously, we have carried out studies using emitting isotope-antibody conjugates (including I-131) to target the dose of radiation to the marrow and, thus, spare normal organs. Previously we have investigated the use of the alpha emitting radionuclide bismuth-213 (Bi-213)and our current studies are investigating the use of astatine-211 (At-211). The alpha emitters have the advantages of a relatively short half-life, high linear energy transfer, and are easier to handle than gamma emitters. We have evaluated a Bi-213 anti-CD45 MAb conjugate for immunosuppression and have shown that this was sufficient conditioning for stable engraftment in the MHC-identical setting. We also have investigated the use of a Bi-213-anti-TCR MAb conjugate to target T cells to eliminate host-versus-graft (HVG) reactions in the MHC-identical setting and have had similar findings. Currently we are investigating this approach using At-211 in the MHC-identical and nonidentical setting.
Our current regimen for hematopoietic cell transplantation in human patients, developed in our preclinical model, uses a non-myeloablative conditioning regimen consisting of fludarabine and 2 Gy of total body irradiation before and mycophenolate mofetil combined with cyclosporine after transplant. This has now been successfully applied to patients with leukemia, lymphoma, multiple myeloma, and other malignant diseases who were too old or medically infirm to be eligible for conventional myeloablative transplants. Both related and unrelated HLA-identical donors are used. Data, thus far, indicate that successful allografts in patients otherwise ineligible for conventional allografting can be done with minimal toxicities. Complete remissions including molecular remissions, have been seen in a substantial number of the patients, indicating that this approach is feasible and may be curative. We are also extending our findings to using donors that are not HLA-identical. Currently we are investigating the role of donor lymphocyte infusion (DLI) for both improvement of low donor chimerism and for treatment of persistant or relapsed disease.
American Society of Clinical Oncology
American Society of Hematology
International Society of Experimental Hematology
A pilot pharmacologic biomarker study in HLA-haploidentical hematopoietic cell transplant recipients.. Cancer chemotherapy and pharmacology. 72(3):607-18.. 2013.
Frequency of allogeneic hematopoietic cell transplantation among patients with high- or intermediate-risk acute myeloid leukemia in first complete remission.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 31(31):3883-8.. 2013.
Non-relapse mortality and mycophenolic acid exposure in nonmyeloablative hematopoietic cell transplantation.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.. 2013.
Donor Lymphocyte Infusion for Relapsed Hematological Malignancies after Allogeneic Hematopoietic Cell Transplantation: Prognostic Relevance of the Initial CD3(+) T Cell Dose.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.. 2013.
High prevalence of potential drug interactions affecting mycophenolic acid pharmacokinetics in nonmyeloablative hematopoietic stem cell transplant recipients.. International journal of clinical pharmacology and therapeutics.. 2013.
Fludarabine and 2-Gy TBI is Superior to 2 Gy TBI as Conditioning for HLA-Matched Related Hematopoietic Cell Transplantation: A Phase III Randomized Trial.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.. 2013.
Costs of second allogeneic hematopoietic cell transplantation.. Transplantation. 96(1):108-15.. 2013.
Allogeneic Hematopoietic Cell Transplantation Following Minimal Intensity Conditioning: Predicting Acute Graft-versus-Host Disease and Graft-versus-Tumor Effects.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.. 2013.
Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 31(12):1530-8.. 2013.
Efficacy of a Viral Load-Based, Risk-Adapted, Preemptive Treatment Strategy for Prevention of Cytomegalovirus Disease after Hematopoietic Cell Transplantation.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 18(11):1687-99.. 2012.
A limited sampling schedule to estimate mycophenolic Acid area under the concentration-time curve in hematopoietic cell transplantation recipients.. Journal of clinical pharmacology. 52(11):1654-64.. 2012.
Association between Calcineurin Inhibitor Blood Concentrations and Outcomes after Allogeneic Hematopoietic Cell Transplantation.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 18(3):414-422.. 2012.
Nonmalignant late effects and compromised functional status in survivors of hematopoietic cell transplantation.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 30(1):71-7.. 2012.