Innovative Compounds, Combination Therapies Improve Care of Patients with Wide Range of Blood Disorders

Dec 08, 2013, 09:00 ET from American Society of Hematology

NEW ORLEANS, Dec. 8, 2013 /PRNewswire-USNewswire/ -- A series of studies presented today during the 55th American Society of Hematology Annual Meeting and Exposition in New Orleans uncover promising efficacy and safety results for several unique compounds and combination treatments, each aimed at improving long-term outcomes for patients with blood disorders ranging from clots to cancer.

Recent advances have helped hematologists better understand the cellular activity of blood cancers and non-malignant blood disorders. These developments have paved the way for the development of new molecules that selectively target disease-causing mechanisms and, as a result, may improve treatment success. Furthermore, researchers are now identifying combinations of existing therapies, in addition to new targeted therapies, that can more effectively prevent disease progression while reducing the toxic side effects of current standard treatments.

The encouraging efficacy of these novel therapies in patients has allowed researchers to focus on developing strategies that aim to increase patients' long-term survival while reducing toxicity. For example, several new investigational therapies being discussed in today's press conference have been designed to target specific proteins on the cell surface that fuel cancer growth. Additional studies look at existing anti-cancer compounds in new ways to better understand drug interactions, reduce toxicity, increase response rates and improve outcomes among patients with disease that might be resistant to current treatments. Yet another study harnesses the therapeutic value of clot-busting snake venom, translating it into a powerful new investigational therapy.

"Our research efforts in hematology continue to focus on identifying 'next-generation' treatments that will make treatment easier and more tolerable for patients with blood disorders," said Joseph Mikhael, MD, moderator of the press conference and Associate Dean of the School of Graduate Medical Education, Deputy Director of Education at Mayo Clinic Cancer Center and Associate Professor of Medicine at Mayo Clinic College of Medicine in Scottsdale, Arizona. "These clever approaches – from selectively interfering with cancer-driving proteins to targeting mechanisms of abnormal cell growth to exploring the utility of purified snake venom as an anticoagulant – exemplify the exciting progress we're making in improving the treatment of hematologic cancers and blood diseases."

This press conference will take place on Sunday, December 8, 2013, at 8:00 a.m. CST.

The First In Vitro and In Vivo Assessment of Anfibatide, a Novel Glycoprotein Ib Antagonist, in Mice and in a Phase I Human Clinical Trial [577]

Using purified snake venom, a team of researchers developed a unique new anti-thrombotic compound known as anfibatide, which is designed to target a specific receptor on the surface of platelets that is instrumental to the formation of blood clots (glycoprotein Ib complex, or GPIb). Researchers initially assessed the investigational compound's clot-busting effects in several in vitro laboratory tests, and then evaluated functional activity in mouse models. After reaching the conclusion that anfibatide may be effective as an anti-thrombotic drug, the team then evaluated its safety and efficacy in a Phase I clinical trial. When tested in 94 healthy volunteers, the compound effectively prevented platelets from sticking together specifically through the GPIb complex, but did not otherwise affect platelet count or significantly prolong bleeding. At the doses investigated, no anti-anfibatide antibodies were detected, and the treatment caused no serious adverse events or deaths among study participants.

"The concept that we can harness something potentially poisonous in nature and turn it into a beneficial therapy is very exciting," said one of the senior investigators Heyu Ni, MD, PhD, of St. Michael's Hospital, the University of Toronto, and Canadian Blood Services. "The fact that this compound only targets the platelet receptor involved in clotting and does not appear to have significant side effects makes it a particularly promising anti-thrombotic therapy."

Dr. Ni will present this study during an oral presentation at 4:30 p.m. CST on Monday, December 9, in Rooms 278-282 of the Ernest N. Morial Convention Center.

Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Siltuximab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients With Multicentric Castleman's Disease [505]

Drugs known as monoclonal antibodies, engineered to target disease-harboring proteins on the surface of cells or to block growth signals in the microenvironment, have demonstrated strong efficacy and safety, and have become more common treatments for blood cancers. Given this success, researchers are experimenting with the use of monoclonal antibodies in rare diseases with limited treatment options. One such disease is multicentric Castleman's disease (MCD), a potentially fatal, incurable disorder with high morbidity believed to be partially mediated by the overproduction of a specific cell signaling molecule known as interleukin-6 (IL-6) that results in the dangerous overgrowth of cells in the lymph nodes.

This study evaluated the safety and efficacy of siltuximab, an investigational monoclonal antibody designed to block the function of IL-6 in an attempt to ameliorate uncontrolled cell growth and control other inflammatory disease symptoms. Investigators enrolled 79 MCD patients in a Phase II trial who were randomized to receive either siltuximab or placebo, in combination with best supportive care, to assess rates of remission and improvement in symptoms. Roughly one-third of patients treated with siltuximab achieved a durable tumor and symptom response whereas none of the placebo-treated patients showed a response. While disease symptoms completely resolved in one-quarter of the siltuximab-treated patients for a median of 1.3 years, this was never observed in patients treated with placebo, indicating that siltuximab led to prolonged duration of disease control. Rates of adverse events were similar between the treatment and placebo groups, despite a two-fold longer duration of treatment in the siltuximab group.

"Based on these promising results, it appears that patients treated with this highly targeted monoclonal antibody approach can potentially experience far superior and equally safe responses than those observed with current conventional treatments," said study author Raymond S. Wong, MBChB, MD, of the Prince of Wales Hospital and the Chinese University of Hong Kong. "If siltuximab gains regulatory approval, this experimental therapy could become the first globally approved treatment for this incurable disease and could potentially transform how patients are treated in the future."

Dr. Wong will present this study during an oral presentation at 2:45 p.m. CST on Monday, December 9, in La Nouvelle Ballroom AB of the Ernest N. Morial Convention Center.  

Initial Phase III Results of the First (Frontline Investigation of Revlimid + Dexamethasone Versus Standard Thalidomide) Trial (MM-020/IFM 07 01) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Stem Cell Transplantation (SCT) [2]

This Phase III trial was designed to compare the efficacy and safety of a combination of two oral drugs, lenalidomide and low-dose dexamethasone (Rd), to a standard combination therapy including melphalan, prednisone, and thalidomide (MPT) used worldwide to treat patients with newly diagnosed multiple myeloma (NDMM). A total of 1,623 NDMM patients ineligible for stem cell transplant due to age or other factors were randomized into three treatment arms: continuous Rd until disease progression, Rd for 72 weeks, or MPT for 72 weeks. After a median follow-up period of 37 months, the study met its primary endpoint by demonstrating that those patients treated with continuous Rd were more than a quarter (28%) less likely to experience disease progression or death than those patients treated with MPT. Further, patients in both Rd treatment arms showed improvements in overall survival, overall response rate, and duration of response. While the safety profiles of the two treatment regimens were similar, patients treated with Rd showed fewer secondary hematologic malignancies than those treated with MPT.

"Traditionally, newly diagnosed patients have received initial, short bursts of treatment, while continuous treatment was reserved for relapsed patients. However, we believe that these new results will help encourage more research on the efficacy and safety of continuous treatment for newly diagnosed patients to help maximize their chances for overall long-term survival," said study author Thierry Facon, MD, of Service des Maladies du Sang, Hôpital Claude Huriez, and CHRU Lille in France. "For some patients with low-risk myeloma, this continuous regimen could make this disease a manageable, chronic condition."

Dr. Facon will present this study during the Plenary Scientific Session at 2:55 p.m. CST on Sunday, December 8, in Hall F of the Ernest N. Morial Convention Center.

Gemtuzumab Ozogamicin (GO) in Children With De Novo Acute Myeloid Leukemia (AML) Improves Event-Free Survival (EFS) by Reducing Relapse Risk – Results From the Randomized Phase III Children's Oncology Group (COG) Trial, AAML0531 [355]

For children diagnosed with cancer, their post-treatment relapse rate is one of the major indicators of their potential for long-term survival. This research program evaluated whether adding the monoclonal antibody gemtuzumab (GO) to standard chemotherapy might improve event-free survival without causing excessive toxicity and mortality in children with acute myeloid leukemia (AML). In this Phase III trial, more than 1,000 children (10 years old on average) were treated with GO or a standard treatment regimen, followed by additional chemotherapy for low-risk patients and stem cell transplants for high-risk patients. Overall, compared with standard regimens, the addition of GO was associated with better disease-free survival (61 vs. 55%) and reduced relapse risk (33 vs. 41%), though it did not significantly improve overall survival (74 vs. 70%).

"These results are encouraging, as combining gemtuzumab with chemotherapy appears to reduce the risk of disease relapse, which translates to an improved event-free survival in children with AML," said study author Alan S. Gamis, MD, MPH, of Children's Mercy Hospital and Clinics in Kansas City, Mo. "Importantly, the therapy seemed to have a particularly lasting effect among those patients who achieved remission in the course of treatment. Though gemtuzumab was previously removed from the market due to lack of clinical value in earlier trials, this growing body of positive data in populations of critical need may be sufficient to bring it back as a commercial treatment option."

Dr. Gamis will present this study during an oral presentation at 10:30 a.m. CST on Monday, December 9, in La Nouvelle Ballroom C of the Ernest N. Morial Convention Center.  

Lenalidomide Promotes CRBN-Mediated Ubiquitination and Degradation of IKZF1 and IKZF3 [LBA-5]

While lenalidomide is an effective treatment commonly used for multiple myeloma and certain B-cell lymphomas, research has yet to fully explain how it works. Using a combination of experiments focused on cellular protein activity, investigators discovered that lenalidomide has a unique mechanism of action for a drug. Specifically, investigators concluded that the drug promotes binding of two lymphoid transcription factors, IKZF1 and IKZF3, to the CRBN-DDB1 ubiquitin ligase. This interaction leads to the selective degradation of these transcription factors, which are essential for multiple myeloma cells. Consistant with this mechanism, the researchers also observed that lenalidomide decreased IKZF1 and IKZF3 levels in human T cells, leading to activation of IL-2 expression, a known effect of the drug.

"Lenalidomide is a unique tool in our treatment arsenal, as we have used it effectively for many years but have not yet fully understood its mechanisms. This research offers a clear illustration of its specific activity in multiple myeloma," said study author Jan Krönke, MD, of Brigham and Women's Hospital in Boston. "Based on these mechanisms, we may be able to design new drugs in our efforts to improve patient outcomes in lymphomas or even in other diseases."

Dr. Krönke will present this study during the Late-Breaking Abstracts Session at 7:30 a.m. CST on Tuesday, December 10, 2013, in Hall F of the Ernest N. Morial Convention Center.

American Society of Hematology 55th Annual Meeting
The study authors and press program moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on leukemia research, new transplantation strategies, novel compounds in development, and progress against sickle cell disease and thalassemia. For the complete annual meeting program and abstracts, visit Follow @ASH_hematology and #ASH13 on Twitter and like ASH on Facebook at for the most up-to-date information about the 2013 ASH Annual Meeting.

The American Society of Hematology (ASH) ( is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 50 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. The official journal of ASH is Blood (, the most cited peer-reviewed publication in the field, which is available weekly in print and online.

SOURCE American Society of Hematology