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
Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients.. Cancer chemotherapy and pharmacology.. 2015.
The association between donor and recipient statin use and infections after allogeneic hematopoietic cell transplantation.. Bone marrow transplantation. 50(3):444-8.. 2015.
Pre-transplant comorbidity burden and post-transplant chronic graft-versus-host disease.. British journal of haematology.. 2015.
In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs.. Mayo Clinic proceedings.. 2015.
Urinary elafin and kidney injury in hematopoietic cell transplant recipients.. Clinical journal of the American Society of Nephrology : CJASN. 10(1):12-20.. 2015.
Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration.. Cancer chemotherapy and pharmacology. 75(1):67-75.. 2015.
Long-term outcomes of patients with persistent indolent B cell malignancies undergoing nonmyeloablative allogeneic transplantation.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 21(2):281-7.. 2015.
Design and Validation of an Augmented Hematopoietic Cell Transplantation-Comorbidity Index Comprising Pretransplant Ferritin, Albumin, and Platelet Count for Prediction of Outcomes after Allogeneic Transplantation.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.. 2015.
Radiolabeled Anti-CD45 Antibody with Reduced-Intensity Conditioning and Allogeneic Transplantation for Younger Patients with Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 20(9). 2014.
Recipient Pretransplant Inosine Monophosphate Dehydrogenase Activity In Nonmyeloablative Hct.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.. 2014.
Central Nervous System Relapse in Adults with Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.. 2014.
Treosulfan, Fludarabine, and 2-Gy Total Body Irradiation Followed by Allogeneic Hematopoietic Cell Transplantation in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.. 2014.
Pharmacokinetic and Pharmacodynamic Analysis of Inosine Monophosphate Dehydrogenase (Impdh) Activity in Mmf-Treated Hct Recipients.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.. 2014.