Project 2: Nonmyeloablative Hematopoietic Cell Allotransplants This project investigates allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning to treat patients with advanced hematological malignancies who are elderly and/or have cormobidities precluding high-dose HCT. Conditioning involves fludarabine (FLU) and 2 Gy total body irradiation (TBI), which lack serious toxicities. Post-grafting immunosuppresssion with mycophenolate motetil and a calcineurin inhibitor both aids engraftment and controls graft-vs.-host disease (GVHD). Graft-vs-tumor (GVT) effects are used to eradicate cancer. Avoiding toxicities has enabled us to surmount age and comorbidity limitations associated with myeloablative regimens. For these reasons and given that median ages of patients at diagnoses of most candidate diseases range from 65-70 years, the number of patients treatable by allogeneic HCT has greatly increased. To date, >1,600 patients have been enrolled on our nonmyeloablative protocols. This project will focus on relapse and acute GVHD.
Specific Aim 1 consists of phase l/ll disease-specific protocols aimed at reducing relapse for patients with chronic lymphocytic lymphoma, acute myelocytic leukemia, and Hodgkin lymphoma. Seventy percent of patients who relapse do so Within the first year. We hypothesize that early relapse is due to blunting of GVT effects by early posttransplant immune compromise. Later, the immune system recovers as immunosuppressive drugs are being tapered or discontinued, thereby allowing powerful GVT effects to develop. The protocols intend to control tumor burden with specific drugs or an antibody-drug conjugate given after HCT, thereby bridging the early, immunocompromised post-transplant period without relapse until immune function recovers and GVT effects occur.
Specific Aim 2 focuses on reducing acute GVHD.
Aim 2 a will use donor statin treatment to prevent acute GVHD among HLA-matched related recipients.
Aim 2 b is based on a just concluded, 3-arm, randomized, phase 11 study involving 208 HLA-matched unrelated recipients, which showed a significant reduction in acute GVHD with added sirolimus;Protocol 2448 is a phase 111 study comparing MMF/CSP/sirolimus to MMF/CSP.
Aim 2 c, HLA-mismatched grafts, will investigate the addition of sirolimus to MMF/CSP. Project 2 is a close collaboration with Project 1 to explore to what extent HLA typing can be refined, thereby extending donor options. A unique aspect of this project is that most of the proposed trials are conducted within a consortium that includes 23 academic centers outside of Seattle.

Public Health Relevance

We have developed a nonmyeloablative regimen for allogeneic HCT to treat patients with advanced, otherwise fatal hematologic cancer who are older or have comorbid conditions. The regimen relies on graft vs. tumor effects to cure cancer. This has enabled treating a previously un-served group of individuals who constitute a majority of patients diagnosed with hematologic malignancies. Initial results among >1,600 patients have been very encouraging. Here, we propose to further improve outcomes by designing disease specific protocols focused on reducing relapse while other protocols are aimed at better GVHD control.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA018029-37A1
Application #
8368293
Study Section
Special Emphasis Panel (ZCA1-GRB-T (M1))
Project Start
1997-12-22
Project End
2017-06-30
Budget Start
2012-09-25
Budget End
2013-06-30
Support Year
37
Fiscal Year
2012
Total Cost
$334,135
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Walter, Roland B; Sandmaier, Brenda M; Storer, Barry E et al. (2015) Number of courses of induction therapy independently predicts outcome after allogeneic transplantation for acute myeloid leukemia in first morphological remission. Biol Blood Marrow Transplant 21:373-8
Mielcarek, Marco; Kirkorian, Anna Yasmine; Hackman, Robert C et al. (2014) Langerhans cell homeostasis and turnover after nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation. Transplantation 98:563-8
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Boyle, Nicole M; Podczervinski, Sara; Jordan, Kim et al. (2014) Bacterial foodborne infections after hematopoietic cell transplantation. Biol Blood Marrow Transplant 20:1856-61
Li, Xiang; Deeg, H Joachim (2014) Murine xenogeneic models of myelodysplastic syndrome: an essential role for stroma cells. Exp Hematol 42:4-10
Fisher, C E; Stevens, A M; Leisenring, W et al. (2014) Independent contribution of bronchoalveolar lavage and serum galactomannan in the diagnosis of invasive pulmonary aspergillosis. Transpl Infect Dis 16:505-10
Raj, Kavita; Pagliuca, Antonio; Bradstock, Kenneth et al. (2014) Peripheral blood hematopoietic stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced-intensity conditioning. Biol Blood Marrow Transplant 20:890-5

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