Latest Findings on Unrelated-Donor BMT, B-Cell Lymphoma Highlight Roswell Park ASH 2015 Presentations
BUFFALO, N.Y. — More than a dozen Roswell Park Comprehensive Cancer Center researchers were invited to present findings at the American Society of Hematology (ASH) 57th Annual Meeting & Exposition, a four-day meeting in Orlando, Fla., that concluded yesterday. Among them were four teams invited to deliver podium presentations detailing what they learned from their latest research projects.
Lara Sucheston-Campbell, PhD, gave an oral presentation on a genome-wide association study (GWAS) conducted to determine whether outcomes for patients receiving blood and marrow transplant (BMT) could be improved by identifying genetic factors in both transplant recipients and their unrelated donors. The matching of HLA, or human leukocyte antigen, protein markers is used to find appropriate donors for blood and marrow transplants, but this study sought a way to identify novel genes that are not in the HLA region that might contribute to transplant-related mortality.
This GWAS, named the DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to One-Year Mortality after BMT) project, is the largest study of its kind and the first GWAS of survival following BMT from an unrelated donor. This effort was supported by the largest Research Project (R01) grant ever awarded to Roswell Park researchers by the National Institutes of Health and one of its member agencies, the National Heart, Lung, and Blood Institute (grant no. R01HL102278).
“Through this study, we identified gene variants outside the HLA region between unrelated BMT donors and their recipients that significantly impact patients’ risk of transplant-related mortality in the first year after BMT,” explains Dr. Sucheston-Campbell, member and Associate Professor of Oncology in the Department of Cancer Prevention and Control. “This finding could aid in the selection of donors, thus potentially improving long-term survival of leukemia patients treated with transplant as curative therapy.”
That presentation was ASH 2015 abstract 61, “Combined Donor and Recipient Non-HLA Genotypes Show Evidence of Genome Wide Association with Transplant Related Mortality (TRM) after HLA-Matched Unrelated Donor Blood and Marrow Transplantation (URD-BMT) (DISCOVeRY-BMT study).”
A podium presentation by Theresa Hahn, PhD, detailed additional findings from the same DISCOVeRY-BMT GWAS. Dr. Hahn and colleagues examined genotype profiles for thousands of BMT recipients and their unrelated donors.
“While survival outcomes after unrelated-donor blood and marrow transplant have significantly improved over the last two decades, there is still room for improvement,” says Dr. Hahn, Professor of Oncology in the Department of Medicine. “Through our retrospective analysis, we identified several markers that appear to be associated with shorter survival after unrelated-donor BMT, and may indicate patients who need to be treated differently with BMT or another treatment approach.”
Dr. Hahn’s presentation was ASH 2015 abstract 397, “Genome-Wide Association Study of Overall and Progression-Free Survival after HLA-Matched Unrelated Donor Blood and Marrow Transplantation (DISCOVeRY-BMT study).”
Kyle Runckel gave the third oral presentation from Roswell Park at the ASH 2015 meeting, reporting findings from a study in diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma. The addition of rituximab as a frontline treatment for this disease, in combination with other agents, has significantly improved outcomes for patients with relapsed/refractory DLBCL, but drug resistance remains an issue for many patients.
“Our findings indicate that a key protein, XIAP, or x-linked inhibitor of apoptosis protein, is critically important in drug-resistant forms of lymphoma because it promotes tumor cell resistance to chemotherapy,” notes Runckel, a predoctoral trainee in the Department of Immunology. “In a preclinical study, we found that blocking XIAP expression in models of drug-resistant lymphoma increased chemotherapy response to the point where treated laboratory models appear to be fully tumor-free. These findings are preliminary and will need to be confirmed through additional experiments, but these results are exciting and very encouraging.”
His presentation was ASH 2015 abstract 590, “Targeting the X-Linked Inhibitor of Apoptosis Protein (XIAP) Can Promote Tumor Cell Death, and Increase the Cytotoxic Effects of Chemotherapy Agents in in Vitro and In Vivo Models of Rituximab-Resistant Lymphoma.”
Adam Utley, a Predoctoral Trainee in the Department of Immunology, was the fourth presenter from Roswell Park. His presentation was ASH 2015 abstract 288, “CD28 Induces Mitochondrial Respiration through Slp-76 in Long-Lived Plasma Cells for Reactive Oxygen Species-Dependant Survival.”
CD28 is a key molecule that facilitates survival of multiple myeloma and antibody-producing plasma cells in bone marrow by inducing metabolic fitness.
“By inhibiting CD 28, we can block this survival signal in the myeloma microenvironment and achieve better patient outcomes,” says Utley. “Furthermore, by targeting the same molecule on antibody secreting plasma cells, we may be able to alleviate antibody-mediated disease such as peanut allergy and lupus."
Additional Roswell Park presentations from the meeting are linked below.
Presented by Alyssa Aldridge, an undergraduate student in the lab of Sarah Holstein, MD, PhD:
- Abstract 3247, Effects of Novel Tropolones with Selective HDAC Inhibitor Activity in Myeloma Cells. This summer research project was supported by funding from the National Cancer Institute of the National Institutes of Health (award number R25CA181003).
Presented by Bora Baysal, MD, PhD, Associate Professor of Medicine in the Department of Pathology and Laboratory Medicine:
- Abstract 998, Oxygen Sensing By Succinate Dehydrogenase Regulates Transcriptional Response to Hypoxia in Monocytes
Presented by Maria Bhatti, MD, Clinical Fellow in the Department of Pediatrics:
- Abstract 1558, PI3K/Akt/mTOR Pathway Inhibition in Chemotherapy-Sensitive and -Resistant Models of Burkitt Lymphoma
Presented by Alyssa Clay, Predoctoral Trainee in the Department of Cancer Prevention and Control:
- Abstract 2621, Evidence for Heterogeneous Genetic Associations with Acute Lymphoblastic Leukemia (ALL) By Cytogenetics and Sex in High-Risk Patients Treated with Matched Unrelated Donor Allogeneic Blood or Marrow Transplant (URD-BMT)
Presented by Jason Den Haese, PhD, Research Technologist in the Department of Medicine:
- Abstract 1391, Functional Genomics and Computational Approaches Identify Novel Small Molecules Targeting Quiescent Leukemia Stem Cells
Presented by Christopher Dougher, Predoctoral Trainee in the Department of Immunology:
- Abstract 2374, Palbociclib (PD-0332991), a Potent Selective CDK4/6 Inhibitor, Overcomes Therapy-Resistant and Sensitizes Diffuse Large B-Cell Lymphoma Pre-Clinical Models to Chemo-Reagents
Presented by Elizabeth Griffiths, MD, Associate Professor of Oncology in the Department of Medicine:
- Abstract 2537, Induction of Cancer Testis Antigen Expression in Circulating Acute Myeloid Leukemia Blasts Following Hypomethylating Agent Monotherapy
- Abstract 2873, NY-ESO-1 Vaccination in Combination with Decitabine for Patients with MDS Induces CD4+ and CD8+ T-Cell Responses
Presented by Juan Gu, PhD, Postdoctoral Associate in the Department of Medicine
- Abstract 4008, Metformin Induces p53-Dependent Mitochondrial Stress in Therapy-Sensitive and -Resistant Lymphoma Pre-Clinical Model and Primary Patients Sample with B-Cell Non-Hodgkin Lymphoma (NHL)
- Abstract 3997, Palbociclib (PD-0332991), a Potent Selective CDK4/6 Inhibitor, Overcomes Therapy-Resistant and Sensitizes Diffuse Large B-Cell Lymphoma Pre-Clinical Models to Chemo-Reagents
- Abstract 2761, JQ1, a Potent c-MYC Inhibitor Overcomes Rituximab-Chemotherapy Resistance in Lymphoma Pre-Clinical Models
Presented by Monica Reddy Muppidi, MD, Clinical Fellow in the Department of Medicine:
- Abstract 1341, CLAG±M (cladribine, cytarabine, granulocyte colony stimulating factor ± mitoxantrone) Results in High Response Rates in Older Patients with Secondary and Relapsed/Refractory Acute Myeloid Leukemia - a Single Institute Experience
Presented by Jayakymar Nair, PhD, Scientist with the Department of Immunology:
- Abstract 4184, JQ1, a Potent c-MYC Inhibitor Overcomes Rituximab-Chemotherapy Resistance in Lymphoma Pre-Clinical Models
Presented by Kyle Runckel, Predoctoral Trainee in the Department of Immunology:
- Abstract 590, Targeting the X-Linked Inhibitor of Apoptosis Protein (XIAP) Can Promote Tumor Cell Death, and Increase the Cytotoxic Effects of Chemotherapy Agents in In Vitro and In Vivo Models of Rituximab-Resistant Lymphoma
Presented by Pallawi Torka, MD, Clinical Fellow in the Department of Medicine
- Abstract 3975, Augmenting Neutrophil Function By Administration of Peg-Filgrastim Potentiates Rituximab and Is Safe in Patients with Indolent B-Cell Non-Hodgkin Lymphomas: Results of a Phase II Study
- Abstract 3173, Effect of Immune Reconstitution on Survival after Autologous Hematopoietic Cell Transplant for B-Cell Non-Hodgkin Lymphoma
Presented by Eunice Wang, MD, Acting Chief, Leukemia Service, and Associate Professor of Oncology in the Department of Medicine:
- Abstract 2491, Plasma Vincristine Levels Are 100-Fold Higher with Marqibo®(Vincristine Sulfate LIPOSOME Injection) in Place of Standard Vincristine in Combination Chemotherapy of Patients ≥ 60 Years Old with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)
- Abstract 2566, Phase 1 Study of CB-839, a First-in-Class, Orally Administered Small Molecule Inhibitor of Glutaminase in Patients with Relapsed/Refractory Leukemia
Presented by Qunling Zhang, MD, PhD, formerly a visiting physician at Roswell Park:
- Abstract 4006, Phase 1 Study of CB-839, a First-in-Class, Orally Administered Small Molecule Inhibitor of Glutaminase in Patients with Relapsed/Refractory Leukemia
The mission of Roswell Park Comprehensive Cancer Center is to understand, prevent and cure cancer. Founded in 1898, Roswell Park is one of the first cancer centers in the country to be named a National Cancer Institute-designated comprehensive cancer center and remains the only facility with this designation in Upstate New York. The Institute is a member of the prestigious National Comprehensive Cancer Network, an alliance of the nation’s leading cancer centers; maintains affiliate sites; and is a partner in national and international collaborative programs. For more information, visit www.roswellpark.org, call 1-800-ROSWELL (1-800-767-9355) or email AskRoswell@Roswellpark.org. Follow Roswell Park on Facebook and Twitter.
Annie Deck-Miller, Senior Media Relations Manager