PROJECT 3: ALLOGENEIC HCT FORHEMATOLOGIC MALIGNANCIES: IMMUNE MANIPULATIONS We have translated a novel approach at allogeneic hematopoietic cell transplantation (HCT) into the clinic to treat patients with hematologic malignancies. The approach uses 2 Gy total body irradiation (TBI) with or without fludarabine (Flu;90 mg/m2) before and immunosuppression with mycophenolate mofetil and cyclosporine (CSP), after HCT for control of both engraftment and graft-versus-host disease (GVHD). With this approach, the burden of tumor eradication has been shifted from the conventional high-dose cytotoxic conditioning to the HCT donors'immune cells (graft-versus-tumor [GVT] effect). Impressive antitumor responses have been seen among almost all of the disease categories studied. However, relapse of disease continues to be a major contributor to poor outcomes in high risk patients. The tempo of donor natural killer (NK) cell recovery after HCT appeared correlated with relapse risk. This finding has influenced the design of trials in Specific Aim 1 proposing donor NK cell infusions to reduce relapse. Encouraged by results inHLA- matched related and unrelated HCT, we have expanded the donor pool to include HLA-haploidentical donors. This, in combination with NK cell infusions, should provide for GVT effects.
Specific Aim 2 addresses the issue of nonrelapse mortality (NRM). Retrospective findings of increased NRM in patients given Flu are being addressed in a phase III trial to determine whether Flu is needed in addition to 2 Gy TBI to condition heavily pretreated patients. GVHD and its extended treatment with immunosuppressive drugs also caused NRM. In order to reduce GVHD, tacrolimus has been substituted for CSP in a phase II study, and early results look promising. For acute myelocytic leukemias, outcomes in elderly patients and those with comorbidities were not different from concurrently transplanted younger patients given myeloablative conditioning regimens. Based on these findings, we have initiated a phase III study comparing myeloablative and nonmyeloablative conditioning in younger patients with myeloid malignancies (Specific Aim 3). During the last grant period, we assessed the impact of comorbidities on survival and cure. After initially using the Charlson Co-morbidity Index, we developed a hematopoietic cell transplantation-specific index (HCT-Cl), which seemed to have higher discriminative capacity. In order to validate the HCT-Cl, we propose to address multi-center issues, as well as inter-rater reproducibility in future studies (Specific Aim 4). 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. In addition, the use of HLA-haploidentical donors will extend the option of HCT to a greater number of patients, including ethnic minorities.

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National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1-RPRB-J)
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Fred Hutchinson Cancer Research Center
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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
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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
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