Late-Breaking Clinical Trials Present Clinic-Ready Advances for Non-Malignant Diseases

New tools and approaches poised to improve diagnostics and care for millions worldwide

(San Diego, December 4, 2018) — Four late-breaking studies being presented today during the 60th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego offer groundbreaking solutions to challenges in diagnosing and managing bleeding and clotting and genetic blood disorders.

“The approaches outlined in these important studies have the potential to benefit a very large number of patients over a very short timeline,” said press briefing moderator Mark Crowther, MD, of McMaster University in Ontario. “They illustrate the revolution in genetic and molecular technologies, which have traditionally been applied primarily to oncology drug development, are how they are now being applied broadly to non-malignant hematologic diseases, which are far more common.”

The studies present tools that are practical, effective, and feasible for implementation.

• Two studies present new insights on the use of direct oral anticoagulants (DOACs), a newer type of anticoagulant that is taken in pill form instead of via injection. In one study, a protocol guides the management of these common drugs around the time of surgery in patients with atrial fibrillation. A second study supports the use of DOACs in patients being treated for cancer in an outpatient setting.
• A third study reports that a new test for sickle cell disease can be used to rapidly screen newborns and is suitable for deployment in low-resource countries, where the disease is prevalent and deadly.
• In a fourth study, a precision medicine approach offers a promising new treatment option for infants born with the rare and often deadly blood disorder hemophagocytic lymphohistiocytosis.

This embargoed press conference will take place on Monday, December 3, 8:00 a.m. PST in Room 22, San Diego Convention Center.

Simple Approach to Pausing Direct Oral Anticoagulants for Surgery Shown Safe and Effective [LBA-5]

Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study: A Perioperative Management Plan for Patients with Atrial Fibrillation who are Receiving a Direct Oral Anticoagulant

A new trial offers the most definitive evidence to date regarding how patients taking DOACs for atrial fibrillation should manage their anticoagulant around the time of an elective surgery or procedure. The study suggests patients can safely stop taking DOACs for one day before and after procedures with a low risk of bleeding and for two days before and after procedures with a higher bleeding risk, which experts believe could help establish an important standard for patient care.

Anticoagulants, which reduce the formation of blood clots, are commonly prescribed for atrial fibrillation, an abnormal heart rhythm that increases the risk of stroke. Increasingly, the newer DOAC blood thinners are being prescribed, yet there is little information about how the regimen should be altered when patients are having surgery or other procedures. Appropriately pausing this medication around the time of surgery is important to minimize the risk of bleeding while continuing to manage the risk of clots, which can lead to stroke and other complications.

Procedures for pausing conventional blood thinners such as warfarin are well established, but there has been little evidence to inform guidelines related to the newer DOACs. This trial is the largest to date that focuses on this question, according to researchers. As the use of DOACs has grown rapidly in the past few years, conflicting guidance on pausing them for surgery has created confusion for both doctors and patients.

“We hope this study will provide the foundation for a simple and safe standard of care and offer clear, evidence-based guidance that can be used consistently across different medical specialties, said lead study author James Douketis, MD, of McMaster University in Hamilton, Ontario, Canada.”

The researchers hypothesized that holding the drug for one or two days before and after the procedure would be safe and effective.

The trial enrolled 3,007 patients at 23 sites in the United States, Canada, and Europe who were taking any of three most commonly used DOACs—apixaban, dabigatran, or rivaroxaban—for atrial fibrillation and were scheduled to have an elective surgery or procedure.

For procedures with a low bleeding risk, such as a colonoscopy or hernia repair, patients were instructed to stop their anticoagulant for one day before and after surgery. For procedures with a higher risk of bleeding, such as major cancer, heart, or orthopedic surgery, or any procedure involving a spinal anesthetic, patients were asked to pause their anticoagulant for two days before and after the procedure.

Patients were not given heparin or any other blood thinners once they had stopped taking their direct oral anticoagulant. The researchers followed up with patients weekly for 30 days to track rates of major bleeding and clots in the veins or arteries.

The results showed the protocol was safe, with less than 2 percent of participants experiencing major bleeding and less than 1 percent experiencing a clot. Blood samples taken just before surgery indicated the vast majority of patients—more than 90 percent overall and nearly 99 percent of those undergoing high risk surgery—had minimal or no anticoagulant left in the blood at the time of surgery.

The results appeared to be relatively consistent across the different anticoagulant medications, Dr. Douketis said. The researchers plan to analyze subgroups for further insights on specific anticoagulants.

The study was jointly funded by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada.

James Douketis, MD, McMaster University, will present this study during the late-breaking abstracts session on Tuesday, December 4, 2018, at 7:30 a.m. PST at the San Diego Convention Center, Hall AB.

Cancer Patients Show Reduced Risk of Harmful Clots While Taking Direct Oral Anticoagulants

Rivaroxaban Thomboprophylaxis in High-Risk Ambulatory Cancer Patients Receiving Systemic Therapy: Results of a Randomized Clinical Trial (CASSINI) [LBA-1]

A new study suggests taking a DOAC) can reduce the risk of harmful blood clots in patients undergoing cancer treatments without substantially increasing the risk of bleeding problems.

Blood clots in veins and arteries are a common complication from cancer and its treatments, and thrombotic events such as pulmonary embolism, stroke, and heart attack are the second leading cause of death among cancer patients. Anticoagulants, or blood thinners, are commonly administered in the hospital setting to reduce the risk of these clots, which often start in veins deep in the legs or arms (a condition known as deep vein thrombosis, or DVT). However, anticoagulants are not frequently prescribed for cancer patients to take at home.

“Since almost all chemotherapy is done in the outpatient setting, giving prophylactic anticoagulants only when patients are in the hospital doesn’t prevent a majority of the clots, most of which occur in the outpatient setting,” said lead study author Alok A. Khorana, MD, of Cleveland Clinic Lerner College of Medicine and Case Western Reserve University.

Previous studies have shown that self-administering a daily injection of the blood thinner heparin at home can reduce the risk of clots in cancer patients, but doctors are often reticent to prescribe this cumbersome and costly preventive regimen to patients undergoing cancer treatment, particularly those who aren’t thought to face a particularly high risk of clots.

This new study is the first to assess the use of DOACs, taken as a daily pill, and to restrict the regimen to patients at high risk for clots. It compared rates of thrombotic events in patients randomly assigned to take a placebo or the DOAC rivaroxaban.

The trial did not meet statistical significance for the primary analysis period of 180 days, mainly because a large proportion of patients stopped taking the drug (or placebo) earlier than 180 days. More than half of those assigned to placebo and nearly 44 percent of those assigned to take rivaroxaban stopped the regimen before 180 days, and more than one-third of clotting events occurred after participants had discontinued their assigned regimen. In a pre-specified supportive analysis focused on the period in which participants were actually taking rivaroxaban or placebo, those taking rivaroxaban showed a substantially reduced risk of clotting.

“Despite the fact that the reduction in venous thromboembolism was not statistically significant during the primary analysis period, the drug was clearly effective in reducing the rates of venous thromboembolism on treatment,” said Dr. Khorana. “Taking rivaroxaban worked as long as the patients kept taking it.”

The trial enrolled 1,080 adult patients starting a new systemic cancer treatment, typically chemotherapy. All of the participants faced an increased risk of venous thromboembolism, as indicated by a score of 2 or higher on the Khorana risk scale, which is based on cancer type, blood test results and body mass index. After screening, 841 patients were assigned to take rivaroxaban or placebo daily for up to 180 days.

Researchers tracked thrombotic events and participants underwent an ultrasound of the legs every eight weeks to detect clots that were not symptomatic. At 180 days, rates of clotting events were not statistically significantly different between the rivaroxaban group (just under 6 percent) and the placebo group (about 8.8 percent). However, the difference was more marked during the on-treatment period, during which 2.6 percent of patients taking rivaroxaban and 6.4 percent of patients taking placebo experienced a primary endpoint event.

At 180 days, a composite of clotting events and death from any cause was observed in just over 23 percent of patients on rivaroxaban and 29.5 percent of those on placebo.

Anticoagulants increase the risk of bleeding. While bleeding was more common among those receiving rivaroxaban, rates of bleeding complications were on par with other studies of direct oral anticoagulants and lower than those commonly seen with heparin, according to Dr. Khorana. Just under 2 percent of those taking rivaroxaban and 1 percent of those taking placebo experienced major bleeding, while non-major bleeding occurred in 2.7 percent of those taking rivaroxaban and 2 percent of those taking placebo.

The researchers plan to analyze whether further stratifying patients by risk score or by cancer type could further clarify the benefits of taking DOACs.

The trial was co-sponsored by Bayer and Janssen.

Alok A. Khorana, MD, Cleveland Clinic, will present this study during the late-breaking abstracts session on Tuesday, December 4, 2018, at 7:30 a.m. PST at the San Diego Convention Center, Hall AB.

Inexpensive, Easy-to-Use Test Shows High Accuracy for Sickle Cell Disease Screening

Implementation of a Sickle Cell Disease Screening Initiative in Uganda with HemoTypeSCTM [LBA-3]

A trial in Uganda showed a new test called HemoTypeSCTM was more than 99 percent accurate in detecting sickle cell disease in young children. The test requires only a small drop of blood and returns results in about 10 minutes, making it suitable for routine screening of newborns.

The current gold standard method for sickle cell disease screening is challenging in most low-resource settings due to its cost and requirements for sophisticated equipment and reliable electricity. By contrast, the HemoTypeSC test kit is inexpensive to manufacture (less than $2.00 per test to the end-user), requires no electricity, and can be used without special equipment or training.

Sickle cell disease is an inherited disorder in which an abnormal protein causes red blood cells to malfunction, leading to episodes of severe pain and other serious complications. Although treatments are available to help control the disease, diagnosing sickle cell disease early in life is crucial to patients’ ability to benefit from these treatments before permanent damage occurs.

Sickle cell disease is especially prevalent in sub-Saharan Africa. In Uganda, where the trial was conducted, sickle cell disease accounts for about one in five childhood deaths each year.

For the trial, researchers recruited 1,000 children ages one month to about 5 years old at a typical low-resourced Ugandan medical facility. Each participant’s blood was tested using two methods: the HemoTypeSC test and hemoglobin electrophoresis, considered the gold standard at this facility. HemoTypeSC diagnostic results matched the results of electrophoresis for 998 out of 1,000 children, an accuracy rate of 99.8 percent.

“The fact that HemoTypeSC is so accurate and so cheap and easy to use shows that this test can be implemented as a widespread newborn screening tool in areas of the world that currently don’t screen for sickle cell disease at all, or certainly not in a pervasive fashion,” said study author Erik Serrao, PhD, director of business and product development at Silver Lake Research Corporation in Azusa, CA. “If it were to be widely implemented in newborn screening initiatives in sub-Saharan Africa and India, it could significantly reduce the mortality of the disease when combined with both treatment and counseling. This would potentially save millions of lives over several decades.”

The HemoTypeSC test works by using highly sensitive and specific monoclonal antibodies to detect hemoglobin proteins associated with sickle cell disease. To use the test kit, health care personnel place a small drop of blood into a paper strip, which is then dipped into a few drops of water within a test tube. A test strip containing the antibodies is then added to the test tube, where it encounters the blood, showing a specific test line if the patient has markers for sickle cell disease.

The trial initially showed conflicting results between HemoTypeSC and electrophoresis for two participants. The HemoTypeSC test indicated the children had sickle cell trait, while hemoglobin electrophoresis indicated they had sickle cell disease. Following up, the researchers discovered that the children had been previously diagnosed with sickle cell disease and had been recently transfused with healthy blood. Because both children had recently received blood transfusions and had both normal and sickle hemoglobin in their blood at the time of testing, the HemoTypeSC test correctly diagnosed these children. The electrophoresis method, with its much lower sensitivity, likely could not detect the transfused normal hemoglobin, which was present at an abnormally low level. After accounting for this discrepancy, the trial was determined to show an accuracy rate of 100 percent for the HemoTypeSC test.

HemoTypeSC is approved for sale in Europe, and according to Silver Lake Research projects that the test will be approved across Africa and in India within the coming year.

The study was sponsored by Silver Lake Research Corporation.

Erik Serrao, PhD, Silver Lake Research Corporation, will present this study during the late-breaking abstracts session on Tuesday, December 4, 2018 at 7:30 a.m. PST at the San Diego Convention Center, Hall AB.

Emapalumab Found to be Safe and Effective for Babies with Rare, Life-Threatening Inflammatory Disease

Safety and Efficacy of Emapalumab in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis [LBA-6]

In a phase 2/3 trial, 70 percent of babies with primary hemophagocytic lymphohistiocytosis (HLH) saw substantial improvements in their symptoms when given the experimental treatment emapalumab. Most of the children had failed to respond to conventional treatments, suggesting emapalumab could significantly improve the outlook for babies with HLH who have few other options.

HLH is a rare but life-threatening disease in which the body makes too many activated immune cells. The overactive immune cells cause inflammation and damage the patient’s own tissues and organs. 

Current treatment options are limited. Allogeneic hematopoietic stem cell transplantation can be curative, but finding a donor and arranging a transplant can take some time, and the procedure carries significant risks. A chemo-immunotherapy regimen can help control symptoms, though it has side effects and does not work for all patients. 

Emapalumab is the first monoclonal antibody developed specifically to treat HLH. It is designed to neutralize the cytokine interferon (IFN)-??, a component of the immune system that plays a pivotal role in HLH.

“This study offers important, novel data on how to optimize the management of these patients through an approach of precision medicine, based on the use of a monoclonal antibody targeting the cytokine driving the hyperinflammation typical of the disease,” said lead study author Franco Locatelli, MD, of Bambino Gesù Children’s Hospital IRCCS in Rome, Italy. “Now, hematologists and pediatricians have a new, effective option for controlling disease manifestations and for bridging a child to allogeneic hematopoietic stem cell transplantation, while sparing toxicities associated with conventional therapies.”

The trial enrolled 34 patients treated for HLH in 14 medical centers in Europe and the United States. Most of the children were less than a year old and most (27) had failed to respond to chemo-immunotherapy. Emapalumab was administered intravenously twice a week for four to eight weeks.

The trial’s primary endpoint was patients’ overall response to treatment assessed at the end of the treatment period. Responsiveness was assessed based on indicators of inflammation and disease activity common in HLH, such as fever, enlarged spleen, central nervous system abnormalities, low platelet and neutrophil counts and the presence of certain molecules—ferritin, fibrinogen, and soluble CD25—in the blood.

The trial met its primary endpoint, with 70 percent of babies responding to emapalumab, a proportion substantially higher than the prespecified null hypothesis of 40 percent. Many participants had disappearance of fever after few days of treatment and showed a marked improvement in other symptoms by the end of the trial. Most of the babies were ultimately able to proceed with allogeneic hematopoietic stem cell transplantation with good results.

“Emapalumab is not only able to promote disease control, blunting the exacerbated immune response typical of the disease, but it may also contribute to optimize the post-transplant outcome of patients given allogeneic haematopoietic stem cell transplantation,” said Dr. Locatelli.

The treatment was generally well tolerated, though 27 percent of patients showed mild to moderate infusion-related reactions. Some of the reported adverse events were known effects of other drugs used, or of the disease itself. 

In November 2018, the U.S. Food and Drug Administration approved emapalumab for the treatment of pediatric and adult patients with primary HLH who have treatment-resistant, recurrent, or progressive disease or cannot tolerate conventional HLH therapy.

This trial was sponsored by Novimmune.

Franco Locatelli, MD, Bambino Gesù Children’s Hospital IRCCS, will present this study during the ASH-FDA Joint Symposium on New Drug Approvals in Non-Malignant Hematology on Monday, December 3, 2018, 4:30 p.m. PST at the San Diego Convention Center, Hall AB. 

The embargo will lift at 4:30 p.m. PST on Monday, December 3, the start of the ASH-FDA Joint-Symposium.

He will also present the study during the late-breaking abstracts session on Tuesday, December 4, 2018, at 7:30 a.m. PST at the San Diego Convention Center, Hall AB.

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 large-scale practice-changing clinical trials, lasting results in CAR T-cell therapies, sickle cell disease, and looking to the future in the era of personalized medicine. For the complete annual meeting program and abstracts, visit www.hematology.org/annual-meeting. Follow @ASH_hematology and #ASH18 on Twitter and like ASH on Facebook for the most up-to-date information about the 2018 ASH Annual Meeting.

The American Society of Hematology (ASH) (www.hematology.org) 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 Society publishes Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, as well as the newly launched, online, open-access journal, Blood Advances.

Contacts:

Adam Silverstein, FleishmanHillard
917-697-9313; [email protected]

Stephen Fitzmaurice, ASH
561-506-6890; [email protected]