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.
|Bar, Merav; Flowers, Mary E D; Storer, Barry E et al. (2018) Reversal of Low Donor Chimerism after Hematopoietic Cell Transplantation Using Pentostatin and Donor Lymphocyte Infusion: A Prospective Phase II Multicenter Trial. Biol Blood Marrow Transplant 24:308-313|
|Graves, Scott S; Parker, Maura H; Stone, Diane et al. (2018) Anti-Inducible Costimulator Monoclonal Antibody Treatment of Canine Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 24:50-54|
|McCune, Jeannine S; Storer, Barry; Thomas, Sushma et al. (2018) Inosine Monophosphate Dehydrogenase Pharmacogenetics in Hematopoietic Cell Transplantation Patients. Biol Blood Marrow Transplant 24:1802-1807|
|Maffini, Enrico; Anderson Jr, Larry D; Sandmaier, Brenda M et al. (2018) Non-myeloablative allogeneic hematopoietic cell transplantation for relapsed or refractory Waldenström macroglobulinemia: evidence for a graft-versus-lymphoma effect. Haematologica 103:e252-e255|
|Li, Yawen; Hamlin, Donald K; Chyan, Ming-Kuan et al. (2018) cGMP production of astatine-211-labeled anti-CD45 antibodies for use in allogeneic hematopoietic cell transplantation for treatment of advanced hematopoietic malignancies. PLoS One 13:e0205135|
|Hill, Joshua A; Mayer, Bryan T; Xie, Hu et al. (2017) The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality. Blood 129:2316-2325|
|Venkataraman, G M; Kennedy, L J; Little, M-T E et al. (2017) Thirteen novel canine dog leukocyte antigen-88 alleles identified by sequence-based typing. HLA 90:165-170|
|McDonald, George B; Tabellini, Laura; Storer, Barry E et al. (2017) Predictive Value of Clinical Findings and Plasma Biomarkers after Fourteen Days of Prednisone Treatment for Acute Graft-versus-host Disease. Biol Blood Marrow Transplant 23:1257-1263|
|Hill, Joshua A; Magaret, Amalia S; Hall-Sedlak, Ruth et al. (2017) Outcomes of hematopoietic cell transplantation using donors or recipients with inherited chromosomally integrated HHV-6. Blood 130:1062-1069|
|Green, Damian J; Maloney, David G; Storer, Barry E et al. (2017) Tandem autologous/allogeneic hematopoietic cell transplantation with bortezomib maintenance therapy for high-risk myeloma. Blood Adv 1:2247-2256|
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