Project Summary Dr. Jonathan Webster is an Assistant Professor of Oncology in the Division of Hematologic Malignancies at The Johns Hopkins University School of Medicine. He is a member of the Leukemia Group and has completed the Science of Clinical Investigation curriculum at the Johns Hopkins Bloomberg School of Public Health. His primary mentor, Dr. Richard Jones, is a Professor of Oncology and the Director of the Bone Marrow Transplantation Program. His co-mentor, Dr. Ravi Varadhan, is a Professor of Oncology in the Division of Biostatistics and Bioinformatics. His advisory committee includes Drs. Gojo and Smith, faculty experts in leukemia clinical trials, and Dr. Luznik, a laboratory-based expert in allogeneic blood or marrow transplantation (alloBMT) and immunology. Support from the K08 award will enable Dr. Webster to gain additional research skills, receive mentorship in authoring publications, develop grants, and perform his research project. Dr. Webster's goal is to become an independent investigator and leader in the emerging field of post-alloBMT therapies. The use of nonmyeloablative conditioning (NMAC) coupled with improvements in supportive care and graft-versus-host disease (GVHD) prophylaxis, such as high-dose post-transplantation cyclophosphamide (PTCy), have led disease relapse to overtake transplant-related mortality as the major cause of treatment failure following alloBMT for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Two factors play a particularly important role in post-alloBMT relapse: peri-transplant measurable residual disease (MRD), and the ability of donor T lymphocytes to generate a graft-versus-leukemia (GVL) effect. The prophylactic post-transplant use of targeted therapies reduces relapses in high risk leukemias, but most patients lack targetable mutations. In this application, Dr. Webster proposes to examine a more broadly applicable approach using the bispecific antibodies blinatumomab and flotetuzumab as post-alloBMT maintenance therapy in ALL and AML, respectively. Dr. Webster has significant preliminary data demonstrating the safety of blinatumomab in this setting and the ease with which post-transplant maintenance therapies can be given following PTCy. The overarching goal of this proposal is to decrease relapse following alloBMT in ALL and AML. He will achieve this by: 1. Conducting a clinical trial of blinatumomab as post-transplant maintenance to assess safety and relapse-free survival. 2. Conducting a clinical trial of flotetuzumab in post-transplant patients to assess safety. 3. Assessing the impact of post-transplant maintenance therapies on the activation and expansion of T lymphocytes, T cell receptor (TCR) diversity, T cell gene expression, and the depletion of cells expressing the target antigens (CD19 and CD123). These studies will inform the development of randomized trials of post-transplant maintenance therapies at the cooperative group level. Data regarding the efficacy of post-alloBMT maintenance therapies in patients with peri-transplant MRD will inform future patient selection, while the immunologic correlates may reveal biomarkers of response.

Project Narrative Allogeneic blood or marrow transplantation (AlloBMT) is the most effective consolidation strategy to prevent disease relapse in adults with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) who achieve remission, but the risk of relapse following transplant remains unacceptably high and is now the most significant cause of post-transplant mortality. Newly developed therapies that stimulate the immune system to fight leukemia have proven successful in ALL and AML patients with relapsed disease. The focus of this application is to use these new therapies following alloBMT to prevent relapse of AML and ALL with a long-term goal of identifying the patients in whom such post-transplant therapy is most necessary and successful.