Emerging treatment approaches may reduce the burden of anemia associated with blood disorders by enhancing production of healthy red blood cells, according to data presented today at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition.
Many blood diseases are linked to anemia caused by a deficiency of healthy red blood cells (RBCs). These deficiencies occur either when the body cannot maintain adequate RBC production or, instead of healthy adult RBCs, it produces immature cells that cannot transport oxygen throughout the body. Myelodysplastic syndromes (MDS), beta thalassemia, and sickle cell disease (SCD) are examples of these types of disorders and are associated with moderate to severe anemia.
Many people suffering from anemia are treated with erythropoiesis-stimulating agents (ESAs, which help the bone marrow produce RBCs), or hydroxyurea, a chemotherapy agent that reduces the number of unhealthy cells in the blood. However, patients who do not respond to these agents must rely on regular blood transfusions to maintain proper RBC levels. While effective, transfusions are expensive, time-consuming, and associated with unique complications such as iron overload.
New research being presented today suggests that a new class of agents, known as activin receptor fusion proteins, may reduce the burden of anemia by encouraging healthy RBCs to mature and proliferate, providing a much-needed alternative to current options. Two treatments in this class offer similar mechanisms and are under investigation for use in patients with low-risk MDS and beta-thalassemia. A separate study suggests that a complementary approach using the amino acid L-glutamine may support healthy RBC growth and diminish the complications of anemia with minimal side effects. Finally, a long-term observational analysis characterizes the natural history of SCD, better illustrating the early mortality associated with the disease and identifying opportunities for intervention during the transition from pediatric to adult care.
"Anemia is a persistent burden for many patients with blood disorders, particularly because many of these patients cannot tolerate current treatments or must rely on regular blood transfusions," said Julie Panepinto, MD, MSPH, moderator of the press conference and professor at the Medical College of Wisconsin and Children's Hospital of Wisconsin in Milwaukee. "We are optimistic about new strategies being presented today to support healthy red blood cell production without causing additional complications for these chronically ill patients."
This press briefing will take place on Sunday, December 7, at 8 a.m. PST in rooms 236-238 of Moscone South, East Mezzanine.
Drug Increases Red Blood Cell Production, Reduces Transfusion Burden in Patients with Myelodysplastic Syndromes
An Open-Label, Phase 2, Dose-Finding Study of Sotatercept (ACE-011) in Patients with Low or Intermediate-1 (Int-1)-Risk Myelodysplastic Syndromes (MDS) or Non-Proliferative Chronic Myelomonocytic Leukemia (CMML) and Anemia Requiring Transfusion 
Anemia is the most challenging complication of myelodysplastic syndromes (MDS), one of the most common blood cancers, and determining optimal treatment remains an unmet need. Among several investigational treatments that aim to promote red blood cell (RBC) growth is sotatercept (ACE-011), a drug that has shown efficacy in early studies with healthy volunteers. This drug, an injectable activin type IIa receptor fusion protein, is designed to attach to a molecule that inhibits erythrocyte (immature RBC) production.
In this Phase II clinical trial, the first study to evaluate sotatercept in MDS patients and seeking to determine the optimal dose of the drug, researchers enrolled 54 largely transfusion-dependent patients who had not responded to treatment with erythrocyte-stimulating agents (ESAs) and other available MDS treatments. The treatment was administered once every three weeks for four doses, and was continued among responders. After treatment with the experimental drug, 45 percent of all evaluable patients experienced either a reduced need for transfusions or an increase in hemoglobin levels. In addition, 19 of the 45 patients who were in the highly transfusion-dependent group prior to receiving sotatercept therapy demonstrated a reduced need for transfusions, including five who became transfusion-independent. The majority of patients (5 of 8) in the less-transfusion-dependent group prior to sotatercept therapy achieved both transfusion independence and increased hemoglobin levels. The treatment was generally well tolerated; 37 percent of patients reported one or more treatment-related adverse events.
"This drug shows promise as an agent that may reduce the burden of regular blood transfusions or eliminate this need among anemic, lower-risk MDS patients," said lead study author Rami S. Komrokji, MD, of Moffitt Cancer Center in Tampa, FL. "Importantly, the response rates are more encouraging in our study than most rates reported with other investigational agents. Larger, randomized studies are necessary to confirm these promising results and evaluate whether a higher dose may provide greater benefit without additional toxicity."
Dr. Komrokji will present this study at 6:00 p.m. PST on Sunday, December 7, in the Poster Hall on Level 1 of Moscone West.
Drug Boosts Hemoglobin Levels, Decreasing Transfusion Burden in Beta-Thalassemia Patients
ACE-536 Increases Hemoglobin and Decreases Transfusion Burden and Serum Ferritin in Adults with Beta-Thalassemia: Preliminary Results from a Phase 2 Study 
A second compound in a new class of activin receptor proteins, ACE-536, is under investigation to treat beta-thalassemia, a blood disorder characterized by reduced hemoglobin production. Patients with this condition often do not respond well to conventional erythropoietin-stimulating agents (ESAs).
This ongoing, Phase II dose-finding trial is studying ACE-536 among adults with transfusion-dependent (TD) and non-transfusion dependent (NTD) beta-thalassemia, evaluating the compound's ability to stimulate more effective erythropoiesis. The treatment is injected once every three weeks for up to five doses at sequentially increasing dose levels with a two-month follow up. As of July 2014, preliminary data for 30 patients (7 TD and 23 NTD patients) receiving several dose levels of ACE-536 demonstrated increased hemoglobin levels among the NTD patients and a significant reduction in transfusion burden (greater than 50%) among the TD patients. No serious adverse events were reported to be related to the treatment, and no notable changes in platelets or white blood cell counts were observed.
"While preliminary, these data indicate that ACE-536 may be effective in increasing hemoglobin levels and decreasing transfusion burden in patients with beta-thalassemia," said lead study author Antonio G. Piga, MD, of University Hospital San Luigi Gonzaga in Torino, Italy. "As no treatments are approved for beta-thalassemia, we are optimistic that ongoing studies will support use of this treatment, with the goal of reducing or even eliminating blood transfusions for these patients."
Dr. Piga will present this study at 12:00 noon PST on Sunday, December 7, in the Golden Gate Hall of the San Francisco Marriott Marquis.
L-Glutamine Reduces Pain Crises, Other Common Events Associated with Sickle Cell Disease
A Phase 3 Study of Oral L-Glutamine Therapy for Sickle Cell Anemia and Sickle Beta Thalassemia 
Sickle cell disease (SCD) is a chronic condition with few treatment options available. The most commonly utilized treatment is oral hydroxyurea, but because of its potential severe side effects, it is not appropriate for use among all patients. This study evaluated the use of pharmaceutical-grade
L-glutamine as a new, daily oral treatment option for SCD based upon the theory that it may reduce oxidative stress and therefore decrease the red blood cell (RBC) "sickling" associated with the disease.
To study the efficacy and safety of L-glutamine for SCD, researchers enrolled 230 patients with SCD into a multi-center, Phase III clinical trial. Study participants were randomized to receive daily L-glutamine (152 patients) or placebo (78 patients) for 48 weeks, after which treatment levels were tapered to zero. Researchers observed that patients who received L-glutamine experienced fewer painful crises and a longer time to a pain crisis than patients receiving placebo. Treated patients were also less likely to be hospitalized for their condition (2 vs. 3 events during the study period) and spent less time in the hospital for these events (6.5 vs. 11 days) than those receiving placebo. Importantly, the percentage of patients experiencing acute chest syndrome, a severe complication of SCD, was less than half among the L-glutamine group compared to the placebo group (11.9% vs. 26.9%). The treatment was well tolerated, as safety profiles were similar among the treatment and placebo groups.
"These findings support the use of L-glutamine in SCD patients, as it appears to safely reduce the most common events associated with the disease," said lead study author Yutaka Niihara, MD, of Emmaus Medical, Inc. in Torrance, CA. "Unlike more intense regimens that require infusions and regular monitoring, this approach could offer a very simple oral alternative, making it particularly compelling."
Dr. Niihara will present this study at 4:30 p.m. PST on Sunday, December 7, in the Golden Gate Hall of the San Francisco Marriott Marquis.
Study Provides Accurate, Modern Natural History of Survival in Sickle Cell Disease
Survival into Adulthood in Sickle Cell Disease from the Dallas Newborn Cohort 
Despite advancements in treatments for sickle cell disease (SCD) that have improved outcomes, early mortality remains a critical issue, and accurate survival estimates are difficult to determine because of the lack of long-term follow up on this patient population.
To better illustrate the experience of sickle cell patients and identify risk factors for early death, the Dallas Newborn Cohort (DNC) was created to follow every infant born in Texas with SCD and receiving treatment at the University of Texas Southwestern Medical Center and Children's Medical Center Dallas. Since its inception in 1983, the DNC has followed 1,214 patients from birth until their transition to adult care. While previous DNC reports were unable to estimate SCD patient survival into adulthood, in this update the team utilized the National Death Index and medical records from local hospitals to extend survival estimates into adulthood. As of the latest analysis in December 2013, 91 percent of patients in the cohort experienced overall survival to age 25 and four percent of the cohort (53 patients) had died. Predictors for early death included genetic indicators of severe disease, lower baseline hemoglobin, and lower baseline oxygen saturation.
"With real-world data from birth to adulthood in a large group of patients, the DNC provides an accurate, modern picture of the natural history of sickle cell disease," said senior study author Timothy L. McCavit, MD, MS, of UT Southwestern Medical Center in Dallas. "While these patients are living longer with a better prognosis, the acceleration of early mortality in the early 20s illustrates the need to better address patients' transition from pediatric to adult care."
Dr. McCavit will present this study at 4:30 p.m. PST on Monday, December 8, in the Golden Gate Hall of the San Francisco Marriott Marquis.
American Society of Hematology