Nonmyeloablative conditioning with low dose TBI (2 Gy) +/- fludarabine (30 mg/m2 x 3) and post grafting immunosuppression with cyclosporine and mycophenolate mofetil provides reliable engraftment for allogeneic G-CSF mobilized peripheral blood stem cells from HLA matched related or unrelated donors. This results in full donor chimerism and provides immunologic graft-vs-tumor (GVT) effects. Indeed, with this platform, nearly all of the anti-tumor activity comes from GVT immune responses with little contribution from the conditioning regimen. Our results demonstratethat this response may provide long term anti-tumor activity in many patients with B cell malignancies with outstanding activity noted in patients with low-grade non-Hodgkin Lymphoma (NHL), mantle cell NHLand chronic lymphocytic leukemia (CLL). Limitations of this approach were also evident as patients with aggressive, bulky or rapidly proliferating disease may develop tumor progression before the development of, or despite GVT effects. The focus of Project 4 is to augment the anti-tumor effect of nonmyeloablative conditioning for the treatment of B cell malignancies by improving pre-transplant cytoreduction, augmenting allogeneic GVT effects and incorporating additional agents with anti tumor activity, and limited toxicity. Lastly, we plan to expand this approach to patients without HLA matched related or unrelated donors by using a newprotocol that allows successful engraftment of related HLA haploidentical grafts.
The Specific Aims are to use: 1. Tandem transplants using cytoreductive high-dose therapy and autologous hematopoietic cell transplantation (HCT) followed by nonmyeloablative allogeneic HCT from : a. HLA matched allogeneic HCT from related or unrelated donors for lymphoma. b. HLA matched allogeneic HCT from related or unrelated donors followed by maintenance therapy with bortezomib for high risk or relapsed Multiple Myeloma (MM).; c. HLA haploidentical allogeneic HCTfrom related donors for relapsed or refractory lymphoma. 2. Addition of targeted therapies to nonmyeloablative conditioning with Flu/TBI followed by allogeneic HCT from HLA matched related or unrelated donors: a. Monomethyl Aurostatin E conjugated anti-CD30 antibody (SGN35) for relapsed or refractory HL. b. Tyrosine kinase inhibitors for Philadelphia chromosome positive leukemia. c. Anti-CD20 antibody Rituximab for CD20 positive B cell NHL and fludarabine refractory CLL. The public health benefits of this Project are that patients with various malignant blood disorders who . otherwise would have been excluded because of age and comorbidities have benefited from treatment by allogeneic HCT. Inaddition, the use of HLA-haploidentical donors will extend the option of HCT to a greater number of patients, including ethnic minorities.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA078902-15
Application #
8459334
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
15
Fiscal Year
2013
Total Cost
$176,157
Indirect Cost
$96,868
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Walter, R B; Gyurkocza, B; Storer, B E et al. (2015) Comparison of minimal residual disease as outcome predictor for AML patients in first complete remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation. Leukemia 29:137-44
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
Hoffmeister, Paul A; Storer, Barry E; Baker, K Scott et al. (2014) Nephrolithiasis in pediatric hematopoietic cell transplantation with up to 40 years of follow-up. Pediatr Blood Cancer 61:417-23
Mathes, David W; Chang, Jeff; Hwang, Billanna et al. (2014) Simultaneous transplantation of hematopoietic stem cells and a vascularized composite allograft leads to tolerance. Transplantation 98:131-8
Matesan, Manuela; Rajendran, Joseph; Press, Oliver W et al. (2014) 90Y-ibritumomab tiuxetan therapy in allogeneic transplantation in B-cell lymphoma with extensive marrow involvement and chronic lymphocytic leukemia: utility of pretransplantation biodistribution. Nucl Med Commun 35:1132-42
Sorror, Mohamed L; Martin, Paul J; Storb, Rainer F et al. (2014) Pretransplant comorbidities predict severity of acute graft-versus-host disease and subsequent mortality. Blood 124:287-95
Gyurkocza, Boglarka; Sandmaier, Brenda M (2014) Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood 124:344-53
Bethge, W A; Kerbauy, F R; Santos, E B et al. (2014) Extracorporeal photopheresis combined with pentostatin in the conditioning regimen for canine hematopoietic cell transplantation does not prevent GVHD. Bone Marrow Transplant 49:1198-204
Sorror, Mohamed L; Storb, Rainer F; Sandmaier, Brenda M et al. (2014) Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol 32:3249-56
Inamoto, Yoshihiro; Martin, Paul J; Storer, Barry E et al. (2014) Response endpoints and failure-free survival after initial treatment for acute graft-versus-host disease. Haematologica 99:385-91

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