Roswell Park Comprehensive Cancer Center Faculty Members to Present New Findings at 56th ASH Annual Meeting and Exposition

Hematologists to present research on agents for multiple myeloma, acute myeloid leukemia
Sunday, December 7, 2014

BUFFALO, N.Y. — Researchers from Roswell Park Comprehensive Cancer Center (Roswell Park) will present data on the use of specific agents for multiple myeloma and acute myeloid leukemia (AML) at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition, being held in San Francisco on Dec. 6–9, 2014.

Sarah A. Holstein, MD, PhD, a staff physician and Assistant Professor of Oncology in the Department of Medicine, will present data on Saturday, Dec. 6 at 5:30 p.m. highlighting work on the development of agents that disrupt Rab geranylgeranylation and that may serve as potential therapeutic agents for multiple myeloma.

“We have now developed a novel class of potent and specific geranylgeranyl diphosphate synthase inhibitors, the homoisoprenoid triazole bisphosphonates, and have demonstrated that these agents disrupt a number of key cellular processes in myeloma cells,” says Dr. Holstein. “Further testing will help determine whether these agents may be used clinically to treat multiple myeloma and other cancers that are dependent on geranylgeranylated proteins.”

Dr. Holstein’s poster presentation is abstract 2156, “A Novel Class of Geranylgeranyl Diphosphate Synthase Inhibitors: Structure-Activity Relationships of Homoisoprenoid Triazoles in Myeloma Cells.”

On Sunday, Dec. 7 at 6 p.m., Elizabeth A. Griffiths, MD, a staff physician and Assistant Professor within the Department of Medicine, will present phase I data on the safety and tolerability of lenalidomide in combination with cytarabine arabinoside in patients with relapsed or refractory AML. Dr. Griffiths and her colleagues found an overall response rate of 41% with the combination of intermediate-dose cytarabine arabinoside and lenalidomide, which they said suggests no superiority over cytarabine arabinoside alone. They also found that the combination treatment was associated with marked skin and other toxicities at the 25-mg dose level of lenalidomide, precluding dose escalation to the 50-mg dose, which has historically been more active.

“These data will be useful to inform future trials of this combination,” says Dr. Griffiths. “Prior studies have demonstrated activity for lenalidomide in relapsed or refractory acute myeloid leukemia, but our study showed no benefit from the combination of these two drugs over the single-agent response to cytarabine arabinoside.”

Dr. Griffith’s poster presentation is abstract 2318, “A Phase I Study of Lenalidomide and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia.”

Finally, on Sunday, Dec. 7 at 6 p.m., Roswell Park researchers will present data on the effects of two autophagy inhibitors on the sensitivity of AML cells to various therapeutic agents under different oxygen levels. These data revealed that pharmacologic inhibitors of autophagy, a highly regulated process in which cells degrade their unnecessary or dysfunctional cellular components, may improve the ability of standard chemotherapy agents to kill AML cells within the marrow microenvironment.

“Despite high remission rates after chemotherapy, the majority of patients will experience disease recurrence due to chemotherapy-resistant disease,” says study author Eunice S. Wang, MD, a staff physician, Associate Professor of Oncology in the Department of Medicine and Assistant Member of the Institute’s Tumor Immunology Program. “In humans, acute myeloid leukemia cells reside within a bone marrow microenvironment that is relatively low in oxygen. Previous findings have shown that this low-oxygen tumor microenvironment makes standard chemotherapy less effective in killing acute myeloid leukemia cells. Our findings show that acute myeloid leukemia cells survive hypoxia in part by upregulating autophagy.”

Combination treatment with an autophagy inhibitor and cytotoxic chemotherapy significantly enhanced apoptosis and cell death compared with single-agent therapy. The antitumor activity of most of the combination regimens studied was consistently improved under hypoxic conditions compared with normoxic conditions. These data showing how acute myeloid leukemia cells survive in hypoxic microenvironments may eventually lead to clinical trials of novel agents targeting or exploiting these interactions to improve clinical outcomes, according to Dr. Wang.

Master’s-degree student and study first author Dirkje W. Hanekamp, MS, received an ASH Achievement Award for this research done in Dr. Wang’s laboratory. Their poster presentation is abstract 2236, “Autophagy Promotes the Survival and Therapy Resistance of Human Acute Myeloid Leukemia Cells Under Hypoxia.”

In addition, Dr. Wang will lend her AML expertise as chair of an education session entitled “AML in the Elderly Patient” at the annual meeting. Her talk will focus on appropriate treatment options for elderly patients, the population most affected by AML. Although intensive induction chemotherapy induces remission and cure in some patients, it is associated with high mortality and morbidity in others.

Dr. Wang will provide an overview of upfront therapeutic strategies for geriatric AML patients, with emphasis on selecting an appropriate approach based on patient age, performance status, disease biology — in particular, karyotype and molecular aberrations, expected treatment mortality, and outcomes. “As deaths from cardiovascular and other disorders recede, it is expected that more individuals are surviving longer. The median age of presentation of AML is 67 to 70, and the incidence of AML rises acutely for patients in their 70s and 80s,” says Dr. Wang. “Alternate strategies have included supportive care with transfusions, hospice or palliative care, and low-dose cytarabine. In recent years, older AML patients have been offered newer hypomethylating agents approved for myelodysplastic syndrome, such as decitabine and azacitidine. These provide older, less fit AML patients a potentially better tolerated, less aggressive therapeutic alternative.”

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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.

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